Antibacterial oxalidinones

ABSTRACT

Compounds of the formula (I), or a pharmaceutically-acceptable salts, or in-vivo-hydrolysable esters thereo Formula (1): wherein N-HeT is for example triazolyl; Q is for example phenyl or pyridyl, substituted withr; T is for example selected from (TAa1 to TAa12) such as (TAa1) and (TAa5): R 4h , R 5h , R 6h  are for example selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy-carbonyl, (1-4C)alkanoyl and carbamoyl; processes for making them, compositions containing them and their use as antibacterial agents are described.

The present invention relates to antibiotic compounds and in particularto antibiotic compounds containing a substituted oxazolidinone ring.This invention further relates to processes for their preparation, tointermediates useful in their preparation, to their use as therapeuticagents and to pharmaceutical compositions containing them.

The international microbiological community continues to express seriousconcern that the evolution of antibiotic resistance could result instrains against which currently available antibacterial agents will beineffective. In general, bacterial pathogens may be classified as eitherGram-positive or Gram-negative pathogens. Antibiotic compounds witheffective activity against both Gram-positive and Gram-negativepathogens are generally regarded as having a broad spectrum of activity.The compounds of the present invention are regarded as principallyeffective against Gram-positive pathogens.

Gram-positive pathogens, for example Staphylococci, Enterococci, andStreptococci are particularly important because of the development ofresistant strains which are both difficult to treat and difficult toeradicate from the hospital environment once established. Examples ofsuch strains are methicillin resistant staphylococcus (MRSA),methicillin resistant coagulase negative staphylococci (MRCNS),penicillin resistant Streptococcus pneumoniae and multiply resistantEnterococcus faecium.

The major clinically effective antibiotic for treatment of suchresistant Gram-positive pathogens is vancomycin. Vancomycin is aglycopeptide and is associated with various toxicities includingnephrotoxicity. Furthermore, and most importantly, antibacterialresistance to vancomycin and other glycopeptides is also appearing. Thisresistance is increasing at a steady rate rendering these agents lessand less effective in the treatment of Gram-positive pathogens. There isalso now increasing resistance appearing towards agents such asβ-lactams, quinolones and macrolides used for the treatment of upperrespiratory tract infections, also caused by certain Gram negativestrains including H. influenzae and M. catarrhalis.

Certain antibacterial compounds containing an oxazolidinone ring havebeen described in the art (for example, Walter A. Gregory et al in J.Med. Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J. Med. Chem.1992,35, 1156-1165). Such antibacterial oxazolidinone compounds with a5-acetamidomethyl side-chain may be subject to mammalian peptidasemetabolism. Furthermore, bacterial resistance to known antibacterialagents may develop, for example, by (i) the evolution of active bindingsites in the bacteria rendering a previously active pharmacophore lesseffective or redundant, (ii) the evolution of means to chemicallydeactivate a given pharmacophore and/or (iii) the development and/orup-regulation of efflux mechanisms. Therefore, there remains an ongoingneed to find new antibacterial agents with a favourable pharmacologicalprofile, in particular for compounds containing new pharmacophores.

Additionally, certain antibacterial compounds containing anoxazolidinone ring have activity against the enzyme mono-amine oxidase(MAO) , for instance compounds with arnidomethyl or hydroxymethyl sidechains at C-5 of the oxazolidinone ring. This may potentially lead toundesirable properties such as elevation in blood pressure whenadministered to a patient, or potentially cause drug-drug interactions.Therefore, there remains an ongoing need to find new antibacterialagents of the oxazolidinone class with a more favourable profile againstMAO.

We have discovered a new class of antibiotic compounds containing anoxazolidinone ring substituted by a 5-azolylmethyl moiety in which theazole group is linked via a nitrogen atom. These compounds haveparticularly useful activity against Gram-positive pathogens includingMRSA and MRCNS and, in particular, against various strains exhibitingresistance to vancomycin and against E. faecium strains resistant toboth aminoglycosides and clinically used β-lactams.

Accordingly the present invention provides a compound of the formula(I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysableester thereof,

wherein —N-HFI is selected from the structures (Ia) to (If) below:—

Q is selected from Q1 to Q6:—

R₂ and R₃ are independently selected from H, F, Cl, CF₃, OMe, SMe, Meand Et;

-   B, is O or S;-   T is selected from the groups in (TAa1) to (TAa12):    wherein:-   R^(6h) is selected from hydrogen, (1-4C)aLkyl, (1-4C)alkoxycarbonyl,    (1-4C)alkanoyl, carbamoyl and cyano;-   R^(4h) and R^(5h) are independently selected from hydrogen, halo,    trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)_(q)-(q    is 0, 1 or 2), (1-4C)alkanoyl, (1-4C)alkoxycarbonyl,    benzyloxy-(1-4C)alkyl, (2-4C)alkanoylamino, —CONRcRv and —NRcRv    wherein any (1-4C)alkyl group contained in the preceding values for    R^(4h) and R^(5h) is optionally substituted by up to three    substituents independently selected from hydroxy (not on C1 of an    alkoxy group, and excluding geminal disubstitution), oxo,    trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (2-4C)alkanoyloxy,    hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)-(q is 0, 1 or    2), (1-4C)alkylSO2-NRv—, (1-4C)alkoxycarbonyl, -CONRcRv, and —NRcRv    (not on C1 of an alkoxy group, and excluding geminal    disubstitution); wherein Rv is hydrogen or (1-4C)alkyl and Rc is as    hereinafter defined;-   R^(4h) and R^(5h) may further be independently selected from    (1-4C)alkyl {optionally substituted by one, two or three    substituents independently selected from hydroxy (excluding geminal    disubstitution), oxo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy,    (2-4C)alkanoyloxy, phosphoryl [—O-P(O)(OH)₂, and mono- and    di-(1-4C)alkoxy derivatives thereof], phosphiryl [—O-P(OH)2 and    mono- and di-(1-4C)alkoxy derivatives thereof], hydroxyimino,    (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)-(q is 0, 1 or 2),    (1-4C)alkylSO2-NRv—, (1-4C)alkoxycarbonyl, —CONRcRv, —NRcRv    (excluding geminal disubstitution), ORc, and phenyl (optionally    substituted by one, two or three substituents independently selected    from (1-4C)alkyl, (1-4C)alkoxy and halo)}; wherein Rv is hydrogen or    (1-4C)alkyl and Rc is as hereinafter defined; and wherein-   any (1-4C)alkyl group contained in the immediately preceding    optional substituents (when R^(4h) and R^(5h) are independently    (1-4C)alkyl) is itself optionally substituted by up to three    substituents independently selected from hydroxy (not on C1 of an    alkoxy group, and excluding geminal disubstitution), oxo,    trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (2-4C)alkanoyloxy,    hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)-(q is 0, 1 or    2), (1-4C)alkylSO₂-NRv—, (1-4C)alkoxycarbonyl, —CONRcRv, and —NRcRv    (not on C1 of an alkoxy group, and excluding geminal    disubstitution); wherein Rv is hydrogen or (1-4C)alkyl and Rc is as    hereinafter defined;-   or R^(4h) is selected from one of the groups in (TAaa) to (TAab)    below, or (where appropriate) one of R^(4h) and R^(5h) is selected    from the above list of R^(4h) and R^(5h) values, and the other is    selected from one of the groups in (TAaa) to (TAab) below:—

(TAaa) a group of the formula (TAaa1)

wherein Z⁰ is hydrogen or (1-4C)alkyl;

X⁰ and Y⁰ are independently selected from hydrogen, (1-4C)alkyl,(1-4C)alkoxycarbonyl, halo, cyano, nitro, (1-4C)alkylS(O)_(q)-(q is 0, 1or 2), RvRwNSO₂—, trifluoromethyl, pentafluoroethyl, (1-4C)alkanoyl and—CONRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl];

(TAab) an acetylene of the formula —≡—H or —≡—(1-4C)alkyl;

wherein Rc is selected from groups (Rc1) to (Rc2):—

(Rc1) (1-6C)alkyl {optionally substituted by one or more (1-4C)alkanoylgroups (including geminal disubstitution) and/or optionallymonosubstituted by cyano, (1-4C)alkoxy, trifluoromethyl,(1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR1 definedhereinafter), (1-4C)alkylS(O)_(q)-(q is 0, 1 or 2); or, on any but thefirst carbon atom of the (1-6C)alkyl chain, optionally substituted byone or more groups (including geminal disubstitution) each independentlyselected from hydroxy and fluoro, and/or optionally monosubstituted byoxo, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O)_(p)NH— or(1-4C)alkylS(O)_(p)-((1-4C)alkyl)N- (p is 1 or 2)};

(Rc2) R³CO—, R¹³SO₂— or R¹³CS—

wherein R¹³ is selected from (Rc2a) to (Rc2d):—

(Rc2a) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl and —NRvRw[wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl];

(Rc2b) (1-10C)alkyl

{optionally substituted by one or more groups (including geminaldisubstitution) each independently selected from hydroxy, (1-10C)alkoxy,(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy,(1-4C)alkanoyl, carboxy, phosphoryl [—O-P(O)(OH)₂, and mono- anddi-(1-4C)alkoxy derivatives thereof], phosphiryl [—O-P(OH)₂ and mono-and di-(1-4C)alkoxy derivatives thereof], and amino; and/or optionallysubstituted by one group selected from phosphonate [phosphono,—P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivatives thereof],phosphinate [—P(QH)₂ and mono- and di-(1-4C)alkoxy derivatives thereof],cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino,di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylaminocarbonyl,di((1-4C)alkyl)aminocarbonyl, (1-4C)alkylS(O)_(p)NH—,(1-4C)alkylS(O)_(p)-((1-4c)alkyl)N—, fluoro(1-4C)alkylS(O)_(p)NH—,fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, (1-4C)alkylS(O)_(q)— [the(1-4C)alkyl group of (1-4C)alkylS(O)_(q)— being optionally substitutedby one substituent selected from hydroxy, (1-4C)alkoxy, (1-4C)alkanoyl,phosphoryl [—O-P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivativesthereof], phosphiryl [—O-P(OH)₂ and mono- and di-(1-4C)alkoxyderivatives thereof], amino, cyano, halo, trifluoromethyl,(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, carboxy,(1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino,(1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino,(1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl,(1-4C)alkylS(O)_(p)NH—, (1-4C)alkylS(O)_(p)-((1-4C)alkyl)N—, and(1-4C)alkylS(O)_(q)—};

(Rc2c) R¹⁴C(O)O(1-6C)alkyl wherein R¹⁴ is AR1, AR2, (1-4C)alkylamino(the (1-4C)alkyl group being optionally substituted by(1-4C)alkoxycarbonyl or by carboxy), benzyloxy-(1-4C)alkyl or(1-10C)alkyl {optionally substituted as defined for (Rc2b)};

(Rc2d) R¹⁵O— wherein R¹⁵ is benzyl, (1-6C)alkyl {optionally substitutedas defined for (Rc2c) }, or AR2b;

wherein

AR1 is an optionally substituted phenyl or optionally substitutednaphthyl;

AR2 is an optionally substituted 5- or 6-membered, fully unsaturated(i.e with the maximum degree of unsaturation) monocyclic heteroaryl ringcontaining up to four heteroatoms independently selected from O, N and S(but not containing any O—O, O—S or S—S bonds), and linked via a ringcarbon atom, or a ring nitrogen atom if the ring is not therebyquaternised;

AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systemsretaining some, but not the full, degree of unsaturation), linked via aring carbon atom or linked via a ring nitrogen atom if the ring is notthereby quaternised;

AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having nounsaturation), linked via a ring carbon atom or linked via a ringnitrogen atom.

In this specification, where it is stated that a ring may be linked viaan SP2 carbon atom it is to be understood that the ring is linked viaone of the carbon atoms in a C═C double bond.

In this specification the term ‘alkyl’ includes straight chained andbranched structures. For example, (1-6C)alkyl includes propyl, isopropyland tert-butyl. However, references to individual alkyl groups such as“propyl” are specific for the straight chained version only, andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. A similar conventionapplies to other radicals, for example halo(1-4C)alkyl includes1-bromoethyl and 2-bromoethyl.

There follow particular and suitable values for certain substituents andgroups which may be referred to in this specification. These values maybe used where appropriate with any of the values, aspects, claims,definitions and embodiments disclosed hereinbefore, or hereinafter.

Examples of (1-4C)alkyl and (1-5C)alkyl include methyl, ethyl, propyl,isopropyl and t-butyl; examples of (1-6C)alkyl include methyl, ethyl,propyl, isopropyl, t-butyl, pentyl and hexyl; examples of (1-10C)alkylinclude methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyland nonyl; examples of (1-4C)alkanoylamino-(1-4C)alkyl includeformamidomethyl, acetamidomethyl and acetamidoethyl; examples ofhydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of(1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of2-cyano-2-((1-4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and2-cyano-2-ethylethenyl; examples of 2-nitro-2-((1-4C)alkyl)ethenylinclude 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of2-((1-4C)alkylaniinocarbonyl)ethenyl include2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl;examples of (2-4C)alkenyl include allyl and vinyl; examples of(2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoylinclude formyl, acetyl and propionyl; examples of (1-4C)alkoxy includemethoxy, ethoxy and propoxy; examples of (1-6C)alkoxy and (1-10C)alkoxyinclude methoxy, ethoxy, propoxy and pentoxy; examples of(1-4C)alkylthio include methylthio and ethylthio; examples of(1-4C)alkylamino include methylamino, ethylamino and propylamino;examples of di-((1-4C)alkyl)aniino include dimethylamino,N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino anddipropylamino; examples of halo groups include fluoro, chloro and bromo;examples of (1-4C)alkylsulfonyl include methylsulfonyl andethylsulfonyl; examples of (1-4C)alkoxy-(1-4C)alkoxy and(1-6C)alkoxy-(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy,2-ethoxyethoxy and 3-methoxypropoxy; examples of(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy,2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkoxy-(1-4C)alkoxycarbonylinclude methoxymethoxycarbonyl, 2-methoxyethoxycarbonyl,2-ethoxyethoxycarbonyl and 3-methoxypropoxycarbonyl; examples of(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl include2-(methoxyrnethoxy)ethoxycarbonyl, 2-(2-methoxyethoxy)ethoxycarbonyl,3-(2-methoxyethoxy)propoxycarbonyl and 2-(2-ethoxyethoxy)ethoxycarbonyl;examples of (1-4C)alkylS(O)₂amino include methylsulfonylamino andethylsulfonylamino; examples of (1-4C)alkanoylamino and(1-6C)alkanoylamino include formamido, acetamido and propionylamino;examples of (2-4C)alkanoylaniino include acetamido and propionylamino;examples of (1-4C)alkoxycarbonylamino include methoxycarbonylamino andethoxycarbonylarnino; examples of N-(1-4C)alkyl-N-(1-6C)alkanoylaniinoinclude N-methylacetamido, N-ethylacetamido and N-methylpropionamido;examples of (1-4C)alkylS(O)_(p)NH— wherein p is 1 or 2 includemethylsulfinylamino, methylsulfonylamino, ethylsulfinylamino andethylsulfonylamino; examples of (1-4C)alkylS(O)_(p)((1-4C)alkyl)Nwherein p is 1 or 2 include methylsulfinylmethylamino,methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)_(p)NH—wherein p is 1 or 2 include trifluoromethylsulfinylamino andtrifluoromethylsulfonylamino; examples offluoro(1-4C)alkylS(O)p((1-4C)alkyl)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylmethylamino andtrifluoromethylsulfonylmethylamino examples of(1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl andethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl includedi-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl;examples of (1-⁴C)alkylS(O)_(q)— wherein q is 0, 1 or 2 includemethylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl andethylsulfonyl; examples of phenylS(O)_(q) and naphthylS(O)_(q)— whereinq is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl andnaphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively;examples of benzyloxy-(1-4C)alkyl include benzyloxymethyl andbenzyloxyethyl; examples of a (3-4C)alkylene chain are trimnethylene ortetramethylene; examples of (1-6C)alkoxy-(1-6C)alkyl includemethoxymethyl, ethoxymethyl and 2-methoxyethyl; examples ofhydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy;examples of (1-4C)alkylamnino-(2-6C)alkoxy include 2-methylaminoethoxyand 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxyinclude 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples ofphenyl(1-4C)alkyl include benzyl and phenethyl; examples of(1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl;examples of di((1-4C)alkyl)carbamoyl include di(methyl)carbamoyl anddi(ethyl)carbamoyl; examples of hydroxyimino(1-4C)alkyl includehydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl;examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl,ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl;examples of (1-4C)alkoxyimino include methoxyimino and ethoxyiminol;examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl,2-haloethyl, and 3-halopropyl; examples of nitro(1-4C)alkyl includenitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples ofamino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl,1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of(1-4C)alkanesulfonamido include methanesulfonamido andethanesulfonamido; examples of (1-4C)alkylaminosulfonyl includemethylaminosulfonyl and ethylamrinosulfonyl; and examples ofdi-(1-4C)alkylamninosulfonyl include dimethylaminosulfonyl,diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of(1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy andpropylsulfonyloxy; examples of (1-4C)alkanoyloxy include formyloxy,acetoxy, propanoyloxy and butanoyloxy; examples of (2-4C)alkanoyloxyinclude acetoxy, propanoyloxy and butanoyloxy; examples of(1-4C)alkylaminocarbonyl include methylaminocarbonyl andethylaminocarbonyl; examples of di((1-4C)alkyl)aminocarbonyl includedimethylaminocarbonyl and diethylaminocarbonyl; examples of(3-8C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; examples of (4-7C)cycloalkyl include cyclobutyl, cyclopentyland cyclohexyl; examples of di(N-(1-4C)alkyl)aminomethylimino includedimethylaminomethylimino and diethylaminomethylimino.

Particular values for AR2 include, for example, for those AR2 containingone heteroatom, furan, pyrrole, thiophene; for those AR2 containing oneto four N atoms, pyrazole, imidazole, pyridine, pyrimidine, pyrazine,pyridazine, 1,2,3- & 1,2,4-triazole and tetrazole; for those AR2containing one N and one O atom, oxazole, isoxazole and oxazine; forthose AR2 containing one N and one S atom, thiazole and isothiazole; forthose AR2 containing two N atoms and one S atom, 1,2,4- and1,3,4-thiadiazole.

Particular examples of AR2a include, for example, dihydropyrrole(especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridine (especially1,2,5,6-tetrahydropyrid-4-yl).

Particular examples of AR2b include, for example, tetrahydrofuran,pyrrolidine, morpholine (preferably morpholino), thiomorpholine(preferably thiomorpholino), piperazine (preferably piperazino),imidazoline and piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl and 1,4-dioxan-2-yl.

Where optional substituents are listed such substitution is preferablynot geminal disubstitution unless stated otherwise. If not statedelsewhere, suitable optional substituents for a particular group arethose as stated for similar groups herein.

Preferable optional substituents on Ar2b as 1,3-dioxolan4-yl,1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- ordisubstitution by substituents independently selected from (1-4C)alkyl(including geminal disubstitution), (1-4C)alkoxy, (1-4C)alkylthio,acetamido, (1-4C)alkanoyl, cyano, trifluoromethyl and phenyl].

Suitable pharmaceutically-acceptable salts include acid addition saltssuch as methanesulfonate, fumarate, hydrochloride, citrate, maleate,tartrate and (less preferably) hydrobromide. Also suitable are saltsformed with phosphoric and sulfuric acid. In another aspect suitablesalts are base salts such as an alkali metal salt for example sodium, analkaline earth metal salt for example calcium or magnesium, an organicamine salt for example triethyl amine, morpholine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine,tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such aslysine. There may be more than one cation or anion depending on thenumber of charged functions and the valency of the cations or anions. Apreferred pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be preferred whetherpharmaceutically-acceptable or not.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). A prodrug may be used to alter or improvethe physical and/or pharmacokinetic profile of the parent compound andcan be formed when the parent compound contains a suitable group orsubstituent which can be derivatised to form a prodrug. Examples ofpro-drugs include in-vivo hydrolysable esters of a compound of theformula (I) or a pharmaceutically-acceptable salt thereof.

Various forms of prodrugs are known in the art, for examples see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p.113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

Suitable pro-drugs for triazole derivatives include triazoliumsalts eghalides; for example a pro-drug such as:

(Ref: T. Yamazaki et al. 42^(nd) Interscience Conference onAntimicrobial Agents and Chemotherapy, San Diego, 2002; Abstract F820).

Suitable pro-drugs of hydroxy groups are glycosides, for example α- orβ-glucosides, in the D- or L- configuration.

Further suitable pro-drugs of hydroxyl groups are acyl esters ofacetal-carbonate esters of formula RCOOC(R,R′)OCO—, where R is(1-4C)alkyl and R′ is (1-4C)alkyl or H. Further suitable prodrugs arecarbonate and carbamate esters RCOO— and RNHCOO—.

An in-vivo hydrolysable ester of a compound of the formula (I) or apharmaceutically-acceptable salt thereof containing carboxy or hydroxygroup is, for example, a pharmaceutically-acceptable ester which ishydrolysed in the human or animal body to produce the parent acid oralcohol.

Suitable pharmaceutically-acceptable esters for carboxy include(1-6C)alkoxymethyl esters for example methoxymethyl,(1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters forexample 5-methyl-1,3-dioxolan-2-ylmethyl; and(1-6C)alkoxycarbonyloxyethyl esters for example1-methoxycarbonyloxyethyl and may be formed at any carboxy group in thecompounds of this invention.

An in-vivo hydrolysable ester of a compound of the invention or apharmaceutically-acceptable salt thereof containing a hydroxy group orgroups includes inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters) and α-acyloxyalkyl ethers and relatedcompounds which as a result of the in-vivo hydrolysis of the esterbreakdown to give the parent hydroxy group/s. Examples of a-acyloxyalkylethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Aselection of in-vivo hydrolysable ester forming groups for hydroxyinclude (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyland phenylacetyl, (1-10C)alkoxycarbonyl (to give alkyl carbonateesters), di-(1-4C)alkylcarbamoyl andN-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to givecarbamates), di-(1-4C)alkylaminoacetyl, carboxy(2-5C)alkylcarbonyl andcarboxyacetyl. Examples of ring substituents on phenylacetyl and benzoylinclude chloromethyl or aminomethyl, (1-4C)alkylaminomethyl anddi-((1-4C)alkyl)aminomethyl, and morpholino or piperazino linked from aring nitrogen atom via a methylene linking group to the 3- or 4-positionof the benzoyl ring. Other interesting in-vivo hydrolysable estersinclude, for example, R^(A)C(O)O(1-6C)alkyl-CO— (wherein R^(A) is forexample, optionally substituted benzyloxy-(1-4C)alkyl, or optionallysubstituted phenyl; suitable substituents on a phenyl group in suchesters include, for example, 4-(1-4C)piperazino-(1-4C)alkyl,piperazino-(1-4C)alkyl and morpholino-(1-4C)alkyl.

Further suitable in-vivo hydrolysable esters are those formed from aminoacids. For examples, esters formed by reaction of a hydroxy group of acompound with the carboxylic acid of an amino acid. By the term “aminoacid” herein we mean any α- or other amino substituted acid, naturallyoccurring or otherwise ie. non-naturally occurring, and derivativesthereof such as those formed by substitution (for example by alkylationon the nitrogen of the amino group). The use of either a natural or anon-natural amino acid represent particular and independent aspects ofthe invention. Examples of suitable α- amino acids and derivativesthereof, are valine, leucine, iso-leucine, N-methyl isoleucine,N-tert-butyl-isoleucine, lysine, glycine, N-methylglycine, N,N-dimethylglycine, alanine, gluamine, asparagine, proline, and phenylalanine. Inone embodiment, preferred amino acids are naturally occurring a-aminoacids and N-alkylated derivatives thereof.

The use of amino acids having neutral and/or basic side chains representparticular and independent aspects of the invention.

Further suitable in-vivo hydrolysable esters of a compound of theformula (I) are described as follows. For example, a 1,2-diol may becyclised to form a cyclic ester of formula (PD1) or a pyrophosphate offormula (PD2), and a 1,3-diol may be cyclised to form a cyclic ester ofthe formula (PD3):

Esters of compounds of formula (I) wherein the HO— function/s in (PD1),(PD2) and (PD3) are protected by (1-4C)alkyl, phenyl or benzyl areuseful intermediates for the preparation of such pro-drugs.

Further in-vivo hydrolysable esters include phosphoramidic esters, andalso compounds of invention in which any free hydroxy groupindependently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0)ester of the formula (PD4):

For the avoidance of doubt, phosphono is —P(O)(OH)₂;(1-4C)alkoxy(hydroxy)-phosphoryl is a mono-(1-4C)alkoxy derivative of—O-P(O)(OH)₂; and

di-(1-4C)alkoxyphosphoryl is a di-(1-4C)alkoxy derivative of—O-P(O)(OH)₂.

Useful intermediates for the preparation of such esters includecompounds containing a group/s of formula (PD4) in which either or bothof the —OH groups in (PD4) is independently protected by (1-4C)alkyl(such compounds also being interesting compounds in their own right),phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionallysubstituted by 1 or 2 groups independently selected from (1-4C)alkyl,nitro, halo and (1-4C)alkoxy).

Thus, prodrugs containing groups such as (PD1), (PD2), (PD3) and (PD4)may be prepared by reaction of a compound of invention containingsuitable hydroxy group/s with a suitably protected phosphorylating agent(for example, containing a chloro or dialkylaamino leaving group),followed by oxidation (if necessary) and deprotection.

Other suitable prodrugs include phosphonooxymethyl ethers and theirsalts, for example a prodrug of R-OH such as:

When a compound of invention contains a number of free hydroxy groups,those groups not being converted into a prodrug functionality may beprotected (for example, using a t-butyl-dimethylsilyl group), and laterdeprotected. Also, enzymatic methods may be used to selectivelyphosphorylate or dephosphorylate alcohol functionalities.

Where pharmaceutically-acceptable salts of an in-vivo hydrolysable estermay be formed this is achieved by conventional techniques. Thus, forexample, compounds containing a group of formula (PD1), (PD2),(PD3)and/or (PD4) may ionise (partially or fully) to form salts with anappropriate number of counter-ions. Thus, by way of example, if anin-vivo hydrolysable ester prodrug of a compound of invention containstwo (PD4) groups, there are four HO-P— functionalities present in theoverall molecule, each of which may form an appropriate salt (i.e. theoverall molecule may formn, for example, a mono-, di-, tri- ortetra-sodium salt).

When a compound of formula (I) contains a number of free hydroxy group,those groups not being converted into a prodrug functionality may beprotected (for example, using a t-butyl-dimethylsilyl group), and laterdeprotected. Also, enzymatic methods may be used to selectivelyphosphorylate or dephosphorylate alcohol functionalities.

Other interesting in-vivo hydrolysable esters include, for example,those in which Rc is defined by, for example, R¹⁴C(O)O(1-6C)alkyl-CO—(wherein R¹⁴ is for example, benzyloxy-(1-4C)alkyl, or phenyl). Suitablesubstituents on a phenyl group in such esters include, for example,4-(1-4C)piperazino-(1-4C)alkyl, piperazino-(1-4C)alkyl andmorpholino-(1-4C)alkyl.

Where pharmaceutically-acceptable salts of an in-vivo hydrolysable estermay be formed this is achieved by conventional techniques. Thus, forexample, compounds containing a group of formula (PD1), (PD2) andlor(PD3) may ionise (partially or fully) to form salts with an appropriatenumber of counter-ions. Thus, by way of example, if an in-vivohydrolysable ester prodrug of a compound of formula (I) contains two(PD3) groups, there are four HO-P— functionalities present in theoverall molecule, each of which may form an appropriate salt (i.e. theoverall molecule may form, for example, a mono-, di-, tri- ortetra-sodium salt).

In one aspect, suitable pro-drugs of the invention are in-vivohydrolysable esters such as (1-4C)alkyl esters; (1-4C)alkyl esterssubstituted with (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkoxy, carboxy,(1-4C)alkyl esters, amino, (1-4C)alkylamino, di(1-4C)alkylamino,tri(1-4C)alkylamino (thereby containing a quaternised nitrogen atom),aminocarbonyl, carbamates,amides or heterocyclyl groups (for example, anester formed by reaction of a hydroxy group in a compound of formula (I)with methoxy acetic acid, methoxypropionic acid, adipic acidmomethylester, 4-dimethylaminobutanoic acid, 2-methylaminobutanoic acid,5-amino pentanoic acid, β-alanine, N,N-diethylalanine, valine, leucine,iso-leucine, N-methyl isoleucine, N-tert-butyl-isoleucine, lysine,glycine, N,N-dimethyl glycine, alanine, sarcosine, glutamine,asparagine, proline, phenylalanine, nicotinic acid, nicotinic acid-N-oxide, pyrimidine-carboxylic acid (for examplepyrimidine-5-carboxylic acid), pyrazine-carboxylic acid (for examplepyrazine-2-carboxylic acid), or piperidine-4-carboxylic acid);(3-6C)cycloalkyl esters (optionally substituted by a(1-4C)alkoxycarbonyl, alkoxy or carboxy group); carbonates (for example(1-4C)alkylcarbonates and such carbonates substituted by (1-4C)alkoxy ordi(1-4C)alkyl)amino); sulfates; phosphates and phosphate esters; andcarbamates; and pharmaceutically acceptable salts thereof.

Further suitable pro-drugs are those formed by reaction of a hydroxygroup in a compound of formula (I) with carbonates, particularlyalkoxysubstituted alkyl carbonates such as methoxypropylcarbonate.

Further suitable pro-drugs are esters formed by reaction of a hydroxygroup in a compound of formula (1) with methoxy acetic acid,methoxypropionic acid, adipic acid momethylester,4-dimethylaminobutanoic acid, 2-methylaminobutanoic acid, 5-aminopentanoic acid, β-alanine, N,N-diethylalanine, valine, leucine,iso-leucine, N-methyl isoleucine, N-tert-butyl-isoleucine, lysine,glycine, N,N-dimethyl glycine, alanine, sarcosine, glutamine,asparagine, proline, phenylalanine, nicotinic acid, nicotinicacid-N-oxide, pyrimidine-5-carboxylic acid, pyrazine-2-carboxylic acid,or piperidine4-carboxylic acid, 2-carboxy-cyclohexane-1-carboxylic acid;and pharmaceutically acceptable salts thereof.

Particular compounds of the invention are in-vivo hydrolysable estersformed from amino acids, and pharmaceutically acceptable salts thereof.

Further particular compounds of the invention are in-vivo hydrolysableesters formed from 4-dimethylaminobutanoic acid, 2-methylaminobutanoicacid, 5-amino pentanoic acid, β-alanine, N,N-diethylalanine, valine,leucine, iso-leucine, N-methyl isoleucine, N-tert-butyl-isoleucine,lysine, glycine, N,N-dimethyl glycine, alanine, sarcosine, glutamine,asparagine, proline, phenylalanine; and pharmaceutically acceptablesalts thereof.

The compounds of the present invention have a chiral centre at the C-5position of the oxazolidinone ring. The pharmaceutically activeenantiomer is of the formula (IA):

The present invention includes the pure enantiomer depicted above ormixtures of the 5(R) and 5(S) enantiomers, for example a racemicmixture. If a mixture of enantiomers is used, a larger amount (dependingupon the ratio of the enantiomers) will be required to achieve the sameeffect as the same weight of the pharmaceutically active enantiomer. Theenantiomer depicted above may be the 5(R) or 5(S) enantiomer dependingon the nature of the N-HET group (for example, when —N-HBET is imidazoleit is the 5(S) enantiomer).

Furthermore, some compounds of the formula (1) may have other chiralcentres, for example, certain sulfoxide compounds may be chiral at thesulfur atom. It is to be understood that the invention encompasses allsuch optical and diastereo-isomers, and racemic mixtures, that possessantibacterial activity. It is well known in the art how to prepareoptically-active forms (for example by resolution of the racemic form byrecrystallisation techniques, by chiral synthesis, by enzymaticresolution, by biotransformation or by chromatographic separation) andhow to determine antibacterial activity as described hereinafter.

Furthermore, some compounds of the formula (I), for example certainsulfoxide compounds may exist as cis- and trans- isomers. It is to beunderstood that the invention encompasses all such isomers, and mixturesthereof, that possess antibacterial activity.

The invention relates to all tautomeric forms of the compounds of theformula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)may exhibit polymorphism, and that the invention encompasses all suchforms which possess antibacterial activity.

As stated before, we have discovered a range of compounds that have goodactivity against a broad range of Gram-positive pathogens, includingorganisms known to be resistant to most commonly used antibiotics. Theyhave good physical and/or pharmacolcinetic properties.

Particularly preferred compounds of the invention comprise a compound offormula (I), or a pharmaceutically-acceptable salt or an in-vivohydrolysable ester thereof, wherein the substituents Q, —N-HBET (whichmay also be described as HBT herein), T and other substituents mentionedabove have values disclosed hereinbefore, or any of the following values(which may be used where appropriate with any of the definitions andembodiments disclosed hereinbefore or hereinafter):

In one embodiment of the invention are provided compounds of formula(I), in an alternative embodiment are providedpharmaceutically-acceptable salts of compounds of formula (I), in afurther alternative embodiment are provided in-vivo hydrolysable estersof compounds of formula (I), and in a further alternative embodiment areprovided pharmaceutically-acceptable salts of in-vivo hydrolysableesters of compounds of the formula (I).

Preferably Q is selected from Q1, Q2, Q4 and Q6; especially Q1 and Q2;and most preferably Q is Q1.

In one embodiment T is selected from the groups of formula (TAa1) to(TAa12) defined herein. Particular values of T are groups of formula(TAa9 to TAa12).

In another embodiment T is selected from the groups of formula (TAa1) to(TAa8). Particular values of T are groups of the formula (TAa5) to(TAa8).

In a preferred embodiment, T is selected from (TAa1 to TAa4), TAa7 andTAa8. Particular values of T are groups of the formula (TAa1 to TA4).

In another embodiment, T is selected from TAa1, TAa3, TAa5, TAa7 andTAa8. Particular values for T are TAa1, TAa5, TAa7 and TAa8.

Especially preferred is each of these values of T when present in Q1andQ2, particularly in Q1.

Preferably R^(6h) is hydrogen or (1-4C)alkyl, more preferably R^(6h) ishydrogen.

In one embodiment R^(4h) and R^(5h) are independently selected fromhydrogen, halo, cyano, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, —CONRcRv{wherein Rc is hydrogen or (1-4C)allcyl; Rv is hydrogen or (1-4C)alkyl}and (1-4C)alkyl [optionally substituted with hydroxy, cyano, ORc(wherein Rc is selected from Rc1 and Rc2 as hereinbefore defined),phenyl {optionally subsituted by 1, 2 or 3 substituents independentlyselected from (1-4C)alkyl, (1-4C)alkoxy and halo} and (1-4C)alkoxy].

In one embodiment, R^(4h) and R^(5h) are independently selected fromhydrogen, halo, cyano, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, —CONRcRv{wherein Rc is hydrogen or (1-4C)alkyl; Rv is hydrogen or (1-4C)alkyl}and (1-4C)alkyl [optionally substituted with hydroxy, cyano, ORc(wherein Rc is selected from Rc1 and Rc2 as hereinbefore defined),phosphoryl, phenyl {optionally substituted by 1, 2 or 3 substituentsindependently selected from (1-4C)alkyl, (1-4C)alkoxy and halo} and(1-4C)alkoxy];.

In another embodiment, R^(4h) and R^(5h) are independently selected fromhydrogen, cyano, hydroxy(1-4C)alkyl, cyano(1-4C)alkyl,phosphoryl(1-4C)alkyl, benzyl (optionally substituted on the phenyl ringby one substituent selected from halo, methyl and methoxy), (1-4C)alkyl,(1-4C)alkyl substituted with ORc (wherein Rc is R¹³CO and R¹³ isselected from Rc2b), (1-4C)alkanoyl and (1-4C)alkoxycarbonyl.

In a further embodiment, R^(4h) and R^(5h) are independently selectedfrom hydrogen, cyano, hydroxymethyl, cyanomethyl, phosphorylmethyl,methoxybenzyl, methyl, formyl and ethoxycarbonyl.

In a preferred embodiment, R^(4h) is selected from methyl, cyano,formyl, ethoxycarbonyl, hydroxymethyl and phosphorylmethyl; and R^(5h)is selected from hydrogen, methyl, methoxybenzyl and cyanomethyl. WhenR^(4h) and R^(5h) are both present (that is, in TAa5) R^(5h) ispreferably hydrogen or methyl.

When R^(4h) and R^(5h) are independently selected from optionallysubstituted (as defined) (1-4C)alkyl, preferably there are one or twosubstituents, most especially just one substituent; and when theoptional substituent is —CONRcRv or —NRcRv, Rc is preferably hydrogen,(1-4C)alkyl or (1-4C)alkanoyl.

In a further preferred embodiment, R^(4h) is (1-4C)alkyl substitutedwith hydroxy and with ORc, where Rc is selected from any of thedefinitions for Rc given hereinbefore or hereinafter, particularly thosedefinitions for Rc in aspects (c) to (g) below.

The above preferred values of (TAa) are particularly preferred whenpresent in Q1 or Q2, especially Q1. Most preferable is (TAa1) withpreferable R^(4h) substituents as hereinbefore defined.

Preferable values for other substituents (which may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore or hereinafter) are

-   (a) —N-BET is preferably of formula (Ic), (Id) or (If).-   (b) In one aspect preferably one of R² and R³ is hydrogen and the    other fluoro. In another aspect both R² and R³ are fluoro.-   (c) In one aspect Rc is R¹³CO— and R¹³ is selected from    (1-4C)alkoxycarbonyl, hydroxy(1-4C)alkyl, (1-4C)alkyl (optionally    substituted by one or two hydroxy groups, or by a (1-4C)alkanoyl    group), (1-4C)alkylamino, dimethylamino(1-4C)alkyl,    (1-4C)alkoxymethyl, (1-4C)alkanoylmethyl,    (1-4C)alkanoyloxy(1-4C)alkyl, (1-5C)alkoxy and 2-cyanoethyl.-   (d) In another aspect Rc is R¹³CO— and R¹³ is (1-4C)alkyl    substituted with one substituent selected from    (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy,    phosphoryl [—O-P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivatives    thereof], phosphiryl [—O-P(OH)₂ and mono- and di-(1-4C)alkoxy    derivatives thereof], phosphonate [phosphono, —P(O)(OH)₂, and mono-    and di-(1-4C)alkoxy derivatives thereof], phosphinate [—P(OH)₂ and    mono- and di-(1-4C)alkoxy derivatives thereof],    (1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl and    (1-4C)alkoxy-(1 4C)alkoxy-(1-4C)alkoxycarbonyl.-   (e) In a further aspect R¹³ is selected from 1,2-dihydroxyethyl,    1,3-dihydroxyprop-2-yl, 1,2,3-trihydroxyprop-1-yl, methoxycarbonyl,    hydroxymethyl, methyl, methylamino, dimethylaminomethyl,    methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl,    tert-butoxy and 2-cyanoethyl.-   (f) In a further aspect R¹³ is selected from 1,2-dihydroxyethyl,    1,3-dihydroxyprop-2-yl and 1,2,3-trihydroxyprop-1-yl.-   (g) In another aspect preferably R¹³ is hydrogen, (1-10C)alkyl    [optionally substituted by one or more hydroxy] or    R¹⁴C(O)O(1-6C)alkyl.

For compounds of formula (1) preferred values for Rc are those in group(Rc2) when present in any of the definitions herein containing Rc.

Where the number of optional substituents on a group is not otherwisepreferably defined, the preferable number of optional substituents isone.

Especially preferred compounds of the present invention are of theformula (IB):

wherein —N-HET is 1,2,3-triazol-1-yl or tetrazol-2-yl;

-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from (TAa1 to TAa4), TAa5, TAa7 and TAa8; or    pharmaceutically-acceptable salts or in-vivo hydrolysable esters    thereof.

Further especially preferred compounds are of the formula (1B) wherein—N-HET is 1,2,3-triazol-1-yl or tetrazol-2-yl;

-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from TAa1, TAa5, TAa7 and TAa8; or    pharmaceutically-acceptable salts or in-vivo hydrolysable esters    thereof.

Further especially preferred compounds are of the formula (IB) wherein—N-HET is 1,2,3-triazol-1-yl or tetrazol-2-yl;

-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from TAa1, TAa5, TAa7 and TAa8;-   R^(6h) is hydrogen or (1-4C)alkyl;-   R^(4h) and R^(5h) are independently selected from hydrogen, cyano,    hydroxy(l4C)alkyl, cyano(1-4C)alkyl, phosphoryl(1-4C)alkyl, benzyl    (optionally substituted on the phenyl ring by one substituent    selected from halo, methyl and methoxy), (1-4C)alkyl, (1-4C)alkyl    substituted with ORc (wherein Rc is R¹³CO and R¹³ is selected from    Rc2b), (1-4C)alkanoyl and (1-4C)alkoxycarbonyl or    pharmaceutically-acceptable salts or in-vivo hydrolysable esters    thereof.

Further especially preferred compounds are of the formula (IB)

wherein —N-HET is 1,2,3-triazol-1-yl or tetrazol-2-yl;

-   R² and R³ are independently hydrogen or fluoro;-   T is selected from TAa1, TAa5, TAa7 and TAa8;-   R^(4h) (1-4C)alkyl substituted with ORc and hydroxy;    or pharmaceutically-acceptable salts or in-vivo hydrolysable esters    thereof.

Further especially preferred compounds are of the formula (IB)

wherein —N-HBET is 1,2,3-triazol-1-yl or tetrazol-2-yl;

-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from TAa1, TAa5, TAa7 and TAa8;-   R⁶h is hydrogen or methyl;-   R^(4h) is selected from methyl, cyano, formyl, ethoxycarbonyl,    hydroxymethyl and phosphorylmethyl;-   R^(5h) is selected from hydrogen, methyl, methoxybenzyl and    cyanomethyl;    or pharmaceutically-acceptable salts or in-vivo hydrolysable esters    thereof.

In all of the above aspects and preferred compounds of formula (IB),in-vivo hydrolysable esters are preferred where appropriate, especiallyphosphoryl esters (as defined by formulae (PD1)-(PD4) with npd as 1).

In all of the above definitions the preferred compounds are as shown informula (IA), i.e. the pharmaceutically active enantiomer.

Particular compounds of the present invention include each one of theExamples, in particular Example No. 1. Each one of the Examples providesa further independent aspect of the invention.

Process Section:

In a further aspect the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically-acceptablesalt or an in-vivo hydrolysable ester thereof. It will be appreciatedthat during certain of the following processes certain substituents mayrequire protection to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byGreene and Wuts (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method as described in the literature or knownto the skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with minimum disturbance of groups elsewhere in themolecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulfuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

A compound of the formula (I), or a pharmaceutically-acceptable salt oran in vivo hydrolysable ester thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a compound of theformula (I), or a pharmaceutically-acceptable salt or an in vivohydrolysable ester thereof, are provided as a further feature of theinvention and are illustrated by the following representative examples.Necessary starting materials may be obtained by standard procedures oforganic chemistry (see, for example, Advanced Organic Chemistry(Wiley-Interscience), Jerry March). The preparation of such startingmaterials is described within the accompanying non-limiting Examples (inwhich, for example, 3,5-difluorophenyl, 3-fluorophenyl and(des-fluoro)phenyl containing intermediates may all be prepared byanalagous procedures; or by alternative procedures—for example, thepreparation of (T group)-(fluoro)phenyl intermediates by reaction of a(fluoro)phenylstannane with, for example, a pyran or(tetrahydro)pyridine compound, may also be prepared by anion chemistry(see, for example, WO97/30995). Alternatively, necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist. Informationon the preparation of necessary starting materials or related compounds(which may be adapted to form necessary starting materials) may also befound in the following Patent and Application Publications, the contentsof the relevant process sections of which are hereby incorporated hereinby reference: WO 94-13649; WO 98-54161; WO 99-64416; WO 99-64417; WO00-21960; WO 01-40222.

The skilled organic chemist will be able to use and adapt theinformation contained and referenced within the above references, andaccompanying Examples therein and also the Examples herein, to obtainnecessary starting materials, and products.

Thus, the present invention also provides that the compounds of theformula (I) and pharmaceutically-acceptable salts and in-vivohydrolysable esters thereof, can be prepared by a process (a) to (g) asfollows (wherein the variables are as defined above unless otherwisestated):

-   (a) by modifying a substituent in, or introducing a new substituent    into, the substituent group Q of another compound of formula (I)—for    instance by (i) displacement of a functional group from a compound    of formula (I) by another functional group, (ii) by oxidation    or (iii) reduction of a compound of formula (I), by (iv) addition of    a reagent to or (v) elimination of a reagent from a compound of    formula (I), by (vi) metathesis of a compound of formula (I) into a    modified compound of formula (1), or by (vii) rearrangement of a    compound of formula (I) to an isomeric compound of formula (1)    (Scheme I shows two examples drawn from the range of suitable    methods); or-   (b) by reaction of a compound of formula (II):    wherein Y is a displaceable group (which may be preformed, such as    chloro or mesylate, or generated in-situ, for example under    Mitsunobu conditions) with a compound of the formula (III):    —N-HET  (III)    wherein —N-HET (of formula (la) to (If), optionally protected) is    HN-BET (free-base form) or ^(—)N-HET anion formed from the free base    form (Scheme II shows examples drawn from the range of suitable    methods); or-   c) by reaction of a compound of the formula (IV):    Q-Z  (IV)    wherein Z is an isocyanate, amine or urethane group with an epoxide    of the formula (V) wherein the epoxide group serves as a leaving    group at the terminal C-atom and as a protected hydroxy group at the    internal C-atom; or with a related compound of formula (VI) where    the hydroxy group at the internal C-atom is conventionally protected    e.g. with an acetyl group and where the leaving group Y at the    terminal C-atom is a conventional leaving group e.g. a chloro- or    mesyloxy-group.    (Scheme III shows examples drawn from the range of suitable    methods), or (d) (i) by coupling, using catalysis by transition    metals such as palladium(0), of a compound of formula (VII):    wherein Y′ is a group —N-HET as hereinbefore defined, X is a    replaceable substituent—such as chloride, bromide, iodide, or    trifluoromethylsulfonyloxy;    with a compound of the formula (VIII), or an analogue thereof, which    is suitable to give a T substituent as defined by (TAa1-TAa12) in    which the link is via an sp² carbon atom (D═CH═C-Lg where Lg is a    leaving group such as chloride, bromide, iodide, or    trifluoromethylsulfonyloxy; or as in the case of reactions carried    out under Heck reaction conditions Lg may also be hydrogen)    where T₁ and T₂ may be the same or different and comprise a    precursor to a ring of type T as hereinbefore defined, or T₁ and T₂    may together with D form a ring of type T as hereinbefore defined    (Scheme IV shows examples drawn from the range of suitable    methods); (d) (ii) by coupling, using catalysis by transition metals    such as palladium(0), of a compound of formula (VIIA):    wherein Y′ is a group HBET as hereinbefore defined, with a compound    [Aryl]-X    where X is a replaceable substituent - such as chloride, bromide,    iodide, or trifluoromethylsulfonyloxy, or an analogue thereof    (Scheme IV shows an example drawn from the range of suitable    methods);-   (e) Where N-HET is 1,2,3-triazole there is the additional    possibility by cycloaddition via the azide (wherein Y in (II) is    azide), with acetylene or masked acetylene (such as a vinyl sulfone,    a nitroloefin, or an enamine, or a substituted cyclohexa-1,4-diene    derivative (Scheme II shows examples drawn from the range of    suitable methods);-   (f) Where N-BET is 1,2,3-triazole there is the additional    possibility of synthesis with a compound of formula (IX), namely the    arenesulfonylhydrazone of acetaldehyde, by reaction of a compound of    formula (II) where Y=NH₂ (primary amine), as illustrated in Scheme    V.-   (g) Where N-HET is 1,2,3-triazole there is the additional    possibility of regioselective synthesis by cycloaddition via the    azide (wherein Y in (II) is azide) with acetylene using Cu(I)    catalysis in e.g. aqueous alcoholic solution at ambient temperatures    to give the N-1,2,3-triazole, as illustrated in Scheme VI.    and thereafter if necessary: (i) removing any protecting    groups; (ii) forming a pharmaceutically-acceptable salt; (iii)    forming an in-vivo hydrolysable ester.

The main synthetic routes are illustrated in Schemes (I) to (VI) below(with Q as phenyl, and T, R2, R3, and A defined with reference toanalogous substituents defined elsewhere herein). The compounds of theinvention may be prepared by analogous chemistry adapted from theseSchemes. Schemes (II) and (VI) also show the preparation of1,2,3-triazoles via the azide (prepared from the relevant hydroxycompound) and the amine (prepared e.g. from the azide) respectively.

Deprotection, salt formation or in-vivo hydrolysable ester formation mayeach be provided as a specific final process step.

The N-linked hetereocycle can of course be prepared early in the overallsynthesis, and then other functional groups changed.

Where Y is a displaceable group, suitable values for Y are for example,a halogeno or sulfonyloxy group, for example a chloro, bromo,methanesulfonyloxy or toluene-4-sulfonyloxy group.

General guidance on reaction conditions and reagents may be obtained inAdvanced Organic Chemistry, 4^(th) Edition, Jerry March (publisher: J.Wiley & Sons), 1992. Necessary starting materials may be obtained bystandard procedures of organic chemistry, such as described in thisprocess section, in the Examples section or by analogous procedureswithin the ordinary skill of an organic chemist. Certain references arealso provided which describe the preparation of certain suitablestarting materials, for example International Patent ApplicationPublication No. WO 97/37980, the contents of which are incorporated hereby reference. Processes analogous to those described in the referencesmay also be used by the ordinary organic chemist to obtain necessarystarting materials.

-   (a) Methods for converting substituents into other substituents are    known in the art. For example an alkylthio group may be oxidised to    an alkylsulfinyl or alkysulfonyl group, a cyano group reduced to an    amino group, a nitro group reduced to an amino group, a hydroxy    group alkylated to a methoxy group, a hydroxy group thiomethylated    to an arylthiomethyl or a heteroarylthiomethyl group (see, for    example, Tet. Lett., 585, 1972), a carbonyl group converted to a    thiocarbonyl group (eg. using Lawsson's reagent) or a bromo group    converted to an alkylthio group. It is also possible to convert one    Rc group into another Rc group as a final step in the preparation of    a compound of the formula (), for example, acylation of a group of    formula (TC5) wherein Rc is hydrogen.-   (b)( i) Reaction (b)(i) (in which Y is initially hydroxy) is    performed under Mitsunobu conditions, for example, in the presence    of tri-n-butylphosphine and diethyl azodicarboxylate (DEAD) in an    organic solvent such as THF, and in the temperature range 0° C.-60°    C., but preferably at ambient temperature. Details of Mitsunobu    reactions are contained in Tet. Letts., 31, 699, (1990); The    Mitsunobu Reaction, D. L. Hughes, Organic Reactions, 1992, Vol. 42,    335-656 and Progress in the Mitsunobu Reaction, D. L. Hughes,    Organic Preparations and Procedures International, 1996, Vol.28,    127-164.

Compounds of the formula (II) wherein Y is hydroxy may be obtained asdescribed in he references cited herein (particularly in the sectionproceeding the discussion of protecting roups), for example, by reactinga compound of the formula (X) with a compound of formula XI):

wherein R²¹ is (1-6C)alkyl or benzyl and R²² is (1-4C)alkyl or—S(O),(1-4C)alkyl where n is 0, 1 or 2. Preferably R²² is (1-4C)alkyl.

In particular, compounds of the formula (II), (X) and (XI) may beprepared by the skilled man, for example as described in InternationalPatent Application Publication Nos. WO95/07271, WO97/27188, WO 97/30995,WO 98/01446 and WO 98/01447, the contents of which are herebyincorporated by reference, and by analogous processes.

If not commercially available, compounds of the formula (III) may beprepared by procedures which are selected from standard chemicaltechniques, techniques which are analogous to the synthesis of known,structurally similar compounds, or techniques which are analogous to theprocedures described in the Examples. For example, standard chemicaltechniques are as described in Houben Weyl, Methoden der OrganischeChemie, E8a, Pt.I (1993), 45-225, B. J. Wakefield.

-   (b)(ii) Reactions (b)(ii) are performed conveniently in the presence    of a suitable base such as, for example, an alkali or alkaline earth    metal carbonate, alkoxide or hydroxide, for example sodium carbonate    or potassium carbonate, or, for example, an organic amine base such    as, for example, pyridine, 2,6-lutidine, collidine,    4-dimethylaminopyridine, triethylamine, morpholine or    diazabicyclo-[5.4.0]undec-7-ene, the reaction is also preferably    carried out in a suitable inert solvent or diluent, for example    methylene chloride, acetonitrile, tetrahydrofuran,    1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide,    N-methylpyrrolidin-2-one or dimethylsulfoxide at and at a    temperature in the range 25-60° C.

When Y is chloro, the compound of the formula (II) may be formed byreacting a compound of the formula (II) wherein Y is hydroxy (hydroxycompound) with a chlorinating agent. For example, by reacting thehydroxy compound with thionyl chloride, in a temperature range ofambient temperature to reflux, optionally in a chlorinated solvent suchas dichloromethane or by reacting the hydroxy compound with carbontetrachloride/triphenyl phosphine in dichloromethane, in a temperaturerange of 0° C. to ambient temperature. A compound of the formula (II)wherein Y is chloro or iodo may also be prepared from a compound of theformula (II) wherein Y is mesylate or tosylate, by reacting the lattercompound with lithium chloride or lithium iodide and crown ether, in asuitable organic solvent such as TBF, in a temperature range of ambienttemperature to reflux

When Y is (1-4C)alkanesulfonyloxy or tosylate the compound (II) may beprepared by reacting the hydroxy compound with (1-4C)alkanesulfonylchloride or tosyl chloride in the presence of a mild base such astriethylamine or pyridine.

When Y is a phosphoryl ester (such as (PhO)₂-P(O)-O—) or Ph₂-P(O)-O— thecompound (II) may be prepared from the hydroxy compound under standardconditions.

-   (c) Reaction (c) is performed under conditions analogous to those    described in the following references which disclose how suitable    and analogous starting materials may be obtained.

Reaction (c) is especially suitable for compounds in which HET-H is aweakly acidic heterocycle (such as, for example, triazole or tetrazole).

Compounds of the formula Q-Z wherein Z is an isocyanate may be preparedby the skilled chemist, for example by analogous processes to thosedescribed in Walter A. Gregory et al in J. Med. Chem. 1990, 33,2569-2578 and Chung-Ho Park et al in J. Med. Chem. 1992, 35, 1156-1165.Compounds of the formula Q-Z wherein Z is a urethane may be prepared bythe skilled chemist, for example by analogous processes to thosedescribed in International Patent Application Publication Nos. WO97/30995 and WO 97/37980.

A similar reaction to reaction (c) may be performed in which Q-Z whereinZ is a amine group is reacted with the epoxide (optionally in thepresence of an organic base), and the product is reacted with, forexample, phosgene to form the oxazolidinone ring. Such reactions and thepreparation of starting materials in within the skill of the ordinarychemist with reference to the above-cited documents disclosing analogousreactions and preparations.

Epoxides of the formula (V) may be prepared from the correspondingcompound of formula (XII):

Certain such epoxide and alkene intermediates are novel and are providedas a further feature of the invention. Asymmetric epoxidation may beused to give the desired optical isomer. Compounds of formula (VI) maybe obtained from epoxides of formula (V); alternatively compounds offormula (VI) may be used as precursors for epoxides of formula (V)according to the relative ease of synthesis in each case. The skilledchemist will appreciate that the epoxides of formula (V) and thecompounds of formula (VI) are structurally equivalent and the choicebetween them will be made on the grounds of availability, convenience,and cost.

-   (d) The transition metal catalysed coupling reaction to form a C—C    or N—C bond from the corresponding aryl derivatives and the arenes,    heteroarenes, olefins, alkynes, or amines is performed under    conventional conditions (see for instance J.K. Stille, Angew. Chem.    Int. Ed. Eng., 1986, 25, 509-524; N. Miyaura and A. Suzuki, Chem.    Rev., 1995, 95, 22457-2483; D. Baranano, G. Mann, and J.F. Hartwig,    Current Org. Che., 1997, 1, 287-305; S. P. Stanforth, Tetrahedron,    1998, 54, 263-303). The reaction d (ii) may be conveniently carried    out under the conditions described in Tetrahedron Letters. (2001),    42(22), 3681-3684, or in the analogous conventional conditions    described in the above mentioned literature. In such a procedure a    preferred variation of X may be bromine.-   (e) The cycloaddition reaction to form 1,2,3 triazoles from the    corresponding azide is performed under conventional conditions.    Compounds of the formula (II) wherein Y is azide may be obtained as    described in the references cited herein (particularly in the    section proceeding the discussion of protecting groups), for example    from the corresponding compounds in which Y is hydroxy or mesylate.-   (f) The reaction of amnines of formula (II, Y=NH2) with    arenesulfonyl hydrazones to form 1,2,3 triazoles may be carried out    as described in the literature (Sakai, Kunikazu; Hida, Nobuko; Kondo    and Kiyosi: “Reactions of α-polyhalo ketone tosylhydrazones with    sulfide ion and primary amines. Cyclization to 1,2,3-thiadiazoles    and 1,2,3-triazoles.” Bull. Chem. Soc. Jpn. (1986), 59(1), 179-83;    Sakai, Kunikazu; Tsunemoto, Daiei; Kobori, Takeo; Kondo, Kiyoshi;    Hida and Nobuko: 1,2,3-Trihetero 5-membered heterocyclic compounds,    EP 103840 A2 19840328). The leaving groups Y′, Y″ may be chloro or    any other group capable of being eliminated from the arenesulfonyl    hydrazone during the reaction with the amine. The skilled chemist    will also appreciate that a similar reaction may be used to produce    other substituted triazoles suitable for incorporation into related    processes such as reaction with compounds of formula (I) in process    (c).-   g) The reaction of azides of formula (II, Y=N₃) with terminal    alkynes using Cu(I) catalysis to give regioselectively 4-substituted    1,2,3-triazole compounds of formula (I) may be carried out as    described in the literature (for instance V. V. Rostovtsev, L. G.    Green, V. V. Fokin, and K. B. Sharpless, Angew. Chem. Int. Ed.,    2002,41,2596-2599).

The removal of any protecting groups, the formation of apharmaceutically-acceptable salt and/or the formation of an in vivohydrolysable ester are within the skill of an ordinary organic chemistusing standard techniques. Furthermore, details on the these steps, forexample the preparation of in-vivo hydrolysable ester prodrugs has beenprovided in the section above on such esters, and in certain of thefollowing non-limiting Examples.

When an optically active form of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing an optically active starting material (formed, for example, byasymmetric induction of a suitable reaction step), or by resolution of aracemic form of the compound or intermediate using a standard procedure,or by chromatographic separation of diastereoisomers (when produced).Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the formula (1) isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

According to a further feature of the invention there is provided acompound of the formula (I), or a pharmaceutically-acceptable salt, orin-vivo hydrolysable ester thereof for use in a method of treatment ofthe human or animal body by therapy.

According to a further feature of the present invention there isprovided a method for producing an antibacterial effect in a warmblooded animal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound of thepresent invention, or a pharmaceutically-acceptable salt, or in-vivohydrolysable ester thereof.

The invention also provides a compound of the formula (I), or apharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof,for use as a medicament; and for use as an anti-bacterial agent; and theuse of a compound of the formula (I) of the present invention, or apharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof,in the manufacture of a medicament for use in the production of anantibacterial effect in a warm blooded animal, such as man.

In order to use a compound of the formula (I), an in-vivo hydrolysableester or a pharmaceutically-acceptable salt thereof, including apharmaceutically-acceptable salt of an in-vivo hydrolysable ester,(hereinafter in this section relating to pharmaceutical composition “acompound of this invention”) for the therapeutic (includingprophylactic) treatment of mammals including humans, in particular intreating infection, it is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula(I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable saltthereof, including a pharmaceutically-acceptable salt of an in-vivohydrolysable ester, and a pharmaceutically-acceptable diluent orcarrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, (lipid) emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder) or for parenteral administration (for example as asterile aqueous or oily solution for intravenous, subcutaneous,intramuscular or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

A pharmaceutical composition to be dosed intravenously may containadvantageously (for example to enhance stability) a suitablebactericide, antioxidant or reducing agent, or a suitable sequesteringagent.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 1 mgto 1 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 100 mg to about 1 g of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between lmg and lg of a compound of thisinvention, preferably between lOOmg and lg of a compound. Especiallypreferred is a tablet or capsule which contains between 50 mg and 800 mgof a compound of this invention, particularly in the range 100 mg to 500mg.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection, forexample an injection which contains between 0.1% w/v and 50% w/v(between lmghml and 500mg/ml) of a compound of this invention.

Each patient may receive, for example, a daily intravenous, subcutaneousor intramuscular dose of 0.5 mgkg-¹ to 20 mgkg-¹ of a compound of thisinvention, the composition being administered 1 to 4 times per day. Inanother embodiment a daily dose of 5 mgkg-¹ to 20 mgkg-¹ of a compoundof this invention is administered. The intravenous, subcutaneous andintramuscular dose may be given by means of a bolus injection.Alternatively the intravenous dose may be given by continuous infusionover a period of time. Alternatively each patient may receive a dailyoral dose which may be approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day.

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain (iethrough co-formulation) or be co-administered (simultaneously,sequentially or separately) with one or more known drugs selected fromother clinically useful antibacterial agents (for example, β-lactams,macrolides, quinolones or aminoglycosides) and/or other anti-infectiveagents (for example, an antifungal triazole or amphotericin). These mayinclude carbapenems, for example meropenem or imipenem, to broaden thetherapeutic effectiveness. Compounds of this invention may also beco-formulated or co-administered withbactericidal/permeability-increasing protein (BPI) products or effluxpump inhibitors to improve activity against gram negative bacteria andbacteria resistant to antimicrobial agents. Compounds of this inventionmay also be co-formulated or co-administered with a vitamin, for exampleVitamin B, such as Vitamin B2, Vitamin B6, Vitamin B12 and folic acid.Compounds of the invention may also be formulated or co-administeredwith cyclooxygenase (COX) inhibitors, particularly COX-2 inhibitors.

In one aspect of the invention, a compound of the invention isco-formulated with an antibacterial agent which is active againstgram-positive bacteria.

In another aspect of the invention, a compound of the invention isco-formulated with an antibacterial agent which is active againstgram-negative bacteria.

In another aspect of the invention, a compound of the invention isco-administered with an antibacterial agent which is active againstgram-positive bacteria.

In another aspect of the invention, a compound of the invention isco-administered with an antibacterial agent which is active againstgram-negative bacteria.

A pharmaceutical composition to be dosed intravenously may containadvantageously (for example to enhance stability) a suitablebactericide, antioxidant or reducing agent, or a suitable sequesteringagent.

In the above other, pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

Biological Activity:

The pharmaceutically-acceptable compounds of the present invention areuseful antibacterial agents having a good spectrum of activity in vitroagainst standard Gram-positive organisms, which are used to screen foractivity against pathogenic bacteria. Notably, thepharmaceutically-acceptable compounds of the present invention showactivity against enterococci, pneumococci and methicillin resistantstrains of S. aureus and coagulase negative staphylococci, together withhaemophilus and moraxella strains. The antibacterial spectrum andpotency of a particular compound may be determined in a standard testsystem.

The (antibacterial) properties of the compounds of the invention mayalso be demonstrated and assessed in-vivo in conventional tests, forexample by oral and/or intravenous dosing of a compound to awarm-blooded mammal using standard techniques.

The following results were obtained on a standard in-vitro test system.The activity is described in terms of the minimum inhibitoryconcentration (MIC) determined by the agar-dilution technique with aninoculum size of 10⁴ CFU/spot. Typically, compounds are active in therange 0.01 to 256 μg/ml.

Staphylococci were tested on agar, using an inoculum of 10⁴ CFU/spot andan incubation temperature of 37° C. for 24 hours—standard testconditions for the expression of methicillin resistance.

Streptococci and enterococci were tested on agar supplemented with 5%defibrinated horse blood, an inoculum of 10⁴ CFU/spot and an incubationtemperature of 37° C. in an atmosphere of 5% carbon dioxide for 48hours—blood is required for the growth of some of the test organisms.

For example, the following results were obtained for the compound ofExample 1: Organism MIC (μg/ml) Staphylococcus aureus: MSQS 0.5 MRQR 1Streptococcus pneumoniae 0.25 Moraxella catarrhalis 1 Enterococcusfaecium 0.5MSQS = methicillin sensitive and quinolone sensitiveMRQR = methicillin resistant and quinolone resistant

The activity of the compounds of the invention against MAO-A was testedusing a standard in-vitro assay based on human liver enzyme expressed inyeast as described in Biochem. Biophys. Res. Commun. 1991, 181,1084-1088. The compounds of the invention showed decreased MAO-A potencycompared with analogues from the known art with C-5 side chains such asacetamidomethyl or hydroxymethyl. When Ki values were measured in suchan assay as above, Example 2 showed a Ki value of 19 μg/ml compared withthe acetamide analogue with a Ki value of 6 μg/ml; Example 7 showed a Kivalue of 144 μg/ml compared with the acetamide analogue with Ki value of34 μg/ml

Certain intermediates and/or Reference Examples described hereinafterwithin the scope of the invention may also possess useful activity, andare provided as a further feature of the invention.

The invention is now illustrated but not limited by the followingExamples in which unless otherwise stated

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work-up procedures were carried out after removal of residual solids    by filtration;-   (ii) operations were carried out at ambient temperature, that is    typically in the range 18-26° C. and without exclusion of air unless    otherwise stated, or unless the skilled person would otherwise work    under an inert atmosphere;-   (iii) column chromatography (by the flash procedure) was used to    purify compounds and was performed on Merck Kieselgel silica    (Art. 9385) unless otherwise stated;-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structure of the end-products of the invention were    generally confirmed by NMR and mass spectral techniques [proton    magnetic resonance spectra were generally determined in DMSO-d₆    unless otherwise stated using a Bruker DRX-300 spectrometer    operating at a field strength of 300 MHz, or a Bruker DRX-500    spectrometer operating at a field strength of 500 MHz; chemical    shifts are reported in parts per million downfield from    tetramethysilane as an internal standard (δ (delta) scale) and peak    multiplicities are shown thus: s, singlet; d, doublet; AB or dd,    doublet of doublets; dt, doublet of triplets; dm, doublet of    multiplets; t, triplet, m, multiplet; br, broad; fast-atom    bombardment (FAB) mass spectral data were generally obtained using a    Platform spectrometer (supplied by Micromass) run in electrospray    and, where appropriate, either positive ion data or negative ion    data were collected];-   (vi) each intermediate was purified to the standard required for the    subsequent stage and was characterised in sufficient detail to    confirm that the assigned structure was correct; purity was assessed    by HPLC, TLC, or NMR and identity was determined by infra-red    spectroscopy (IR), mass spectroscopy or NMR spectroscopy as    appropriate;-   (vii) in which the following abbreviations may be used:—

DMF is N,N-dimethylformamide; DMA is N,N-dimethylacetamide; TLC is thinlayer chromatography; HPLC is high pressure liquid chromatography; MPLCis medium pressure liquid chromatography; DMSO is dimethylsulfoxide;CDCl₃ is deuterated chloroform; MS is mass spectroscopy; ESP iselectrospray; EI is electron impact; CI is chemical ionisation; EtOAc isethyl acetate; MeOH is methanol; NOE is Nuclear Overhauser Effect.

EXAMPLE 1

(5R)-3-[3-Fluoro-4-(3-methylisoxazol-5-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A suspension of(5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Intermediate 6, 582 mg, 1.50 mmol) in 1,4-dioxane (14 ml) was placedunder argon. Bis(triphenylphospine)palladium (II) chloride (42 mg, 0.060mmol) was added, followed by the dropwise addition of5-(tributylstannyl)-3-methylisoxazole (Sakamoto, T. et al; Tetrahedron,1991, 47, 5111-5118; 0.84 g, 2.25 mmol) in 1,4-dioxane (1 ml). Themixture was heated at 100° C. After approximately 16 hours, the solutionwas concentrated under vacuum. The crude material was dissolved inacetonitrile and washed with hexanes (3×). The acetonitrile phase wasconcentrated under vacuum. Purification by chromatography on silica gelusing EtOAc, followed by recrystallization from EtOAc/MeOH gave 256 mgof the title product.MS (APCI): 344 (MH⁺) for C₁₆H₁₄N₅O₃¹H-NMR 50 MHz (DMSO-d₆) δ: 2.32 (s, 3H); 3.98 (m, 1H); 4.31(t, 1H); 4.89(d, 2H); 5.20 (m, 1H); 6.73 (d, 1H); 7.48 (dd, 1H); 7.66 (dd, 1H); 7.79(s, 1H); 7.93 (t, 1H); 8.20 (s, 1H).The intermediates for this compound were prepared as follows:Intermediate 1: Acetic acid(5R)-3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester

(5R)-3-(3-Fluorophenyl)-5-hydroxymethyloxazolidin-2-one (40 g, 0.189 M,see Upjohn WO 94-13649) was suspended by stirring in dry dichloromethane(400 ml) under nitrogen. Triethylamine (21 g, 0.208 M) and4-dimethylaminopyridine (0.6 g, 4.9 mmol) were added, followed bydropwise addition of acetic anhydride (20.3 g, 0.199 M) over 30 minutes,and stirring continued at ambient temperature for 18 hours. Saturatedaqueous sodium bicarbonate (250 ml) was added, the organic phaseseparated, washed with 2% sodium dihydrogen phosphate, dried (magnesiumsulfate), filtered and evaporated to give the desired product (49.6 g)as an oil.MS (ESP): 254 (MHz for C₁₂H₁₂FNO₄NMR 300 MHz (CDChd3) δ: 2.02 (s, 3H); 3.84 (dd, 1H); 4.16 (t, 1H); 4.25(dd, 1); 4.32 (dd, 1H); 4.95 (m, 1H); 6.95 (td, 1H); 7.32 (d, 1H); 7.43(t, 1H); 7.51 (d, 1H).Intermediate 2: Acetic acid(5R)-3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester

Acetic acid (5R)-3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester(Intermediate 1, 15.2 g, 60 mmol) was dissolved in a mixture ofchloroform (100 ml) and acetonitrile (100 ml) under nitrogen, and silvertrifluoroacetate (16.96 g, 77 mmol) added. Iodine (18.07 g, 71 mmol) wasadded in portions over 30 minutes to the vigorously stirred solution,and stirring continued at ambient temperature for 18 hours. As reactionwas not complete, a further portion of silver trifluoroacetate (2.64 g,12 mmol) was added and stirring continued for 18 hours. Afterfiltration, the mixture was added to sodium thiosulfate solution (3%,200 ml) and dichloromethane (200 ml), and the organic phase separated,washed with sodium thiosulfate (200 ml), saturated aqueous sodiumbicarbonate (200 ml), brine (200 ml), dried (magnesium sulfate),filtered and evaporated. The crude product was suspended in isohexane(100 ml), and sufficient diethyl ether added to dissolve out the brownimpurity while stirring for 1 hour. Filtration gave the desired product(24.3 g) as a cream solid.MS (ESP): 380 (MH⁺) for C₁₂H₁₁FINO₄¹H-NMR 300 MHz (DMSO-d₆) δ: 2.03 (s, 3H); 3.82 (dd, 1H); 4.15 (t, 1H);4.24 (dd, 1H); 4.30 (dd, 1H); 4.94 (m, 1H); 7.19 (dd, 1H); 7.55 (dd,1H); 7.84 (t, 1H).Intermediate 3:(5R)-3-(3-Fluoro-4-iodonhenyl)-5-hydroxymethyloxazolidin-2-one

Acetic acid (5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethylester (Intermediate 2, 30 g, 79 mmol) was treated with potassiumcarbonate (16.4 g, 0.119 mmol) in a mixture of methanol (800 ml) anddichloromethane (240 ml) at ambient temperature for 25 minutes, thenimmediately neutralised by the addition of acetic acid (10 ml) and water(500 ml). The precipitate was filtered, washed with water, and dissolvedin dichloromethane (1.2 L), the solution washed with saturated sodiumbicarbonate, and dried (magnesium sulfate). Filtration and evaporationgave the desired product (23 g).MS (ESP): 338 (MHW) for C₁₀H₉FINO₃¹H-NMR 300 MHz (DMSO-d₆) δ: 3.53 (m, 1H); 3.67 (m, 1H); 3.82 (dd, 1H);4.07 (t, 1H); 4.70 (m, 1H); 5.20 (t, 1H); 7.21 (dd, 1H); 7.57 (dd, 1H);7.81 (t, 1H).Intermediate 4:[(5R)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methylmethanesulfonate

(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one(Intermediate 3, 25.0 g, 74.2 mmol) was stirred in dichloromethane (250ml) at 0° C. Triethylamine (10.5 g, 104 mmol) was added followed bymethanesulfonyl chloride (11.2 g, 89.0 nmmol) and the reaction wasstirred overnight, slowly warming to room temperature. The yellowsolution was diluted with sodium bicarbonate and the compound wasextracted using dichloromethane (3×250 ml). The organic layer was dried(magnesium sulfate), filtered and concentrated to give the desiredproduct as a light yellow solid (30.3 g).MS (ESP): 416 (MH⁺) for C₁₁H₁₁FINO₅S

-   ¹H-NMR 300 MHz (DMSO-d₆): 3.24 (s, 3H); 3.82 (dd, 1H); 4.17 (t, 1H);    4.43-4.52 (m, 2H); 4.99-5.03 (m, 1H); 7.21 (dd, 1H); 7.55 (dd, 1H);    7.83 (t, 1H).    Intermediate 5: (5R)-5-(Azidomethyl)-3-(3-fluoro-4-iodolphenyl)-    1,3-oxazolidin-2-one    [(5R)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl    methanesulfonate (Intermediate 4, 6.14 g, 14.7 mmol) was dissolved    in N,N-dimethylformamide (50 ml). Sodium azide (1.92 g, 29.6 mmol)    was added and the reaction was stirred at 75° C. overnight. The    yellow mixture was poured into half-saturated sodium bicarbonate and    extracted using ethyl acetate. The organic layer was washed three    times with water, dried (magnesium sulfate), filtered, and    concentrated to give the title compound as a yellow solid (4.72 g).    MS (ESP): 363 (MH⁺) for C₁₀H₈FIN₄O₂    ¹H-NMR 300 MHz (DMSO-d₆): 3.72-3.82 (m, 3H); 4.14 (t, 1H); 4.89-4.94    (m, 1H); 7.22 (dd, 1H); 7.57 (dd, 1H); 7.83 (t, 1H).    Intermediate 6:    (5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one    (5R)-5-(Azidomethyl)-3-(3-Fluoro-4-iodophenyl)-1,3-oxazolidin-2-one    (Intermediate 5, 30.3 g, 72.9 mmol) was stirred in 1,4-dioxane.    Bicyclo[2.2.1]hepta-2,5-diene (40.3 g, 437 mmol) was added and the    reaction was heated to 100° C. overnight. The brown mixture was    filtered and the desired compound was obtained as a light brown    solid (14.8 g).    MS (ESP): 389 (MH⁺) for C₁₂H₁₀FIN₄O₂    ¹H-NMR 300 MHz (DMSO-d₆: 3.90 (dd, 1H); 4.23 (t, 1H); 4.84 (d, 2H);    5.11-5.18 (m, 1H), 7.14 (dd, 1H); 7.49 (dd, 1H); 7.76 (s, 1H); 7.82    (t, 1H); 8.17 (s, 1H).

EXAMPLE 2

Ethyl5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazole-3-carboxylate

The procedure is identical to that used in Example 1 except(5R)-3-(3-fluoroiodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Intermediate 6, 582 mg, 1.50 mmol) and ethyl5-(tributylstannyl)isoxazole-3-carboxylate (Sakamoto, T. et al.,Tetrahedron, 1991, 47, 5111-5118); 806 mg, 1.87 mmol) were used asstarting materials. The crude product was purified by chromatography onsilica gel using EtOAc, followed by recrystallization fromacetone/hexanes to give 175 mg of the title product.MS (ESP): 402 (MH⁺) for C₁₈H₁₆FN₅O₅

¹H-NMR 500 MHz (DMSO-d₆) δ: 1.37 (t, 3H); 4.00 (dd, 1H); 4.32 (t, 1H);4.42 (q, 2H); 4.88 (d, 2H); 5.22 (m, 1H); 7.16 (d, 1H); 7.52 (dd, 1H);7.69 (dd, 1H); 7.79 (s, 1H); 8.04 (t, 1H); 8.20 (s, 1H).

EXAMPLE 3

(5R)-3-{3-Fluoro-4-[3-(hydroxymethyl)isoxazol-5-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

Ethyl 5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazole-3-carboxylate(Example 2, 0.4 g, 1.1 mmol) was suspended inmethanol/dichloromethane/dimethylsulfoxide (9 ml:3 ml:1ml). Lithiumborohydride (0.12 g, 5.5 mmol) was added portionwise. The reactionmixture was stirred under nitrogen at room temperature for 1 hour. ThepH was adjusted to pH 34 using 1N hydrogen chloride, the mixture wascooled to 0° C., and the resulting white precipitate was collected bysuction filtration. The white solid was dried in vacuo, giving 0.28 g ofthe desired product.MS (ES+) 360.15 (MH⁺) for C₁₆H₁₄FN₅O₄¹H-NMR 300 MHz (DMSO-d₆) 67: 3.98 (dd, 1H); 4.30 (t, 1H); 4.57 (d, 2H);4.87 (d, 211); 5.20 (m, 1H); 5.55 (t, 1H); 6.80 (d, 1H); 7.48 (dd, 1H);7.65 (dd, 1H); 7.77, (s, 1H); 7.97 (t, 1H); 8.18 (s, 1H).

EXAMPLE 4

(5-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazol-3-yl)methyldihydrogen phosphate

Di-tert-butyl(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazol-3-yl)methylphosphate (Intermediate 7, 0.06 g, 0.1 mmol) was dissolved indichloromethane (1 ml). Trifluoroacetic acid (0.1 ml) was added and thereaction stirred at room temperature under nitrogen for 1.5 hours. Themixture was concentrated in vacuo and then concentrated fromdichloromethane (2×) and diethyl ether (5×) to remove residual acid. Theresulting crude products from two batches were combined and purifiedusing a YMC-ODF AQ column by Gilson reverse phase purification withwater (0.1% trifluoracetic acid) and acetonitrile (0.1% trifluoroaceticacid) as the mobile phase giving 0.06 g of a white solid correspondingto the desired product. To make the disodium salt of the phosphoricacid, the phosphate (0.06 g) was suspended in water (10 ml) andsaturated sodium bicarbonate was added dropwise until a pH of 7-8 wasreached. The water was removed by lyophilization giving a white solid(65 mg) which was 72% desired product and 18% sodium bicarbonate.MS (ES+) 440.19 (MH+) for C₁₆H₁₅FN₅O₇P (phosphoric acid).¹H-NMR 300 MHz (DMSO-d₆) δ: 3.98 (dd, 1H); 4.31 (t, 1H); 4.87 (d, 2H);5.00 (d, 2H); 5.19 (m, 1H); 6.88 (d, 1H); 7.49 (dd, 1H); 7.67 (dd, 1H);7.77, (s, 1H); 7.97 (t, 1H); 8.18 (s, 1H) (2-OH protons obscured bywater peak) (phosphoric acid).Example 4 is an example of a suitable pro-drug for Example 3.The intermediate for this compound was prepared as follows:Intermediate 7: Di-tert-butyl(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazol-3-yl)methylphosphate

(5R)-3-{3-Fluoro-4-[3-(hydroxymethyl)isoxazol-5-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Example 3, 0.1 g, 0.3 mmol) was suspended in dichloromethane (3 ml),and di-tert-butyl-N,N-diethylphosphoramidite (93 μl, 0.3 mmol) and1H-tetrazole (35 mg, 0.5 mmol) were added sequentially. The mixture wasstirred under nitrogen at room temperature for 1.5 hours. Solution wascooled to 0° C. and m-chloroperbenzoic acid (≈70%, 0.1 g, 0.4 mmol) wasadded. The reaction was stirred at 0° C. under nitrogen for 2 hours.After warming to room temperature, saturated sodium bisulfite (3 ml) wasadded and the mixture stirred for 5 minutes followed by dilution withdichloromethane (10 ml). After the layers were separated, the aqueousphase was extracted with dichloromethane (3×10 ml); the combinedorganics were washed with saturated sodium bicarbonate, and brine, anddried over sodium sulfate. The crude material was purified bychromatography (using a Jones Flashmaster) using 0-5% methanol indichloromethane as eluent. Relevant fractions were combined giving 91 mgof the desired product as a white solid.MS (ES+) 552.19 (MH+) for C₂₄H₃₁FN₅O₇P.¹H-NMR 300 MHz (DMSO-d₆) δ: 1.43 (s, 18H); 3.98 (dd, 1H); 4.30 (t, 1H);4.87 (d, 2H); 5.05 (dd, 2H); 5.20 (m, 1H); 6.88 (dd, 1H); 7.50 (dd, 1H);7.66 (dd, 1H); 7.77, (s, 1H); 7.98 (t, 1H); 8.18 (s, 1H).

EXAMPLE 5

1-Methyl-3-{4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-1H-pyrazole-5-carbonitrile

3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5-carbonitrile(Intermediate 14, 00 mg, 0.62 mmol), bicyclo[2.2.1]hepta-2,5-diene (0.70ml, 6.50 mmol) and dioxane (5 ml) were combined and warmed to 90° C. for8 hours. The mixture was evaporated and purified by chromatography onsilica gel eluting with ethyl acetate to give the title compound as anoff-white solid (110 mg).MS (ESP): 350 (M+1) for C₁₇H₁₅N₇O₂¹H-NMR 500 MHz (DMSO-d₆) δ: 3.95 (dd, 1H); 4.08 (s, 3H); 4.30 (t, 1H);4.87 (d, 2H); 5.17 (m, 1H); 7.59 (d, 2H); 7.63 (s, 1H); 7.79 (s, 1H);7.85 (d, 2H); 8.20 (s, 1H).The intermediates for this compound were prepared as follows:Intermediate 8: N-Methoxy-N-methyl-4-nitrobenzamide

N,O-(Dimethyl)hydroxylamine hydrochloride (6.45 g, 65.8 mmol),triethylamine (20 ml, 145 mmol) and 4-dimethylaminopyridine (300 mg, 2.5mmol) were suspended in 150 ml of DMF at 0° C. 4-Nitrobenzoyl chloride(10 g, 53.8 mmol) was added. After 1.5 hours at 0° C., the mixture wasdiluted with ethyl acetate, washed with 1M HCl and then sat. NaCl anddried over sodium sulfate. Filtration and evaporation gave the titlecompound as a light yellow solid (8.51 g).¹H-NMR 500 MHz (DMSO-d₆) δ: 3.31 (s, 3H); 3.34 (s, 3H); 7.84 (d, 2H);8.32 (d, 2H).Intermediate 9: 4,4-Diethoxy-1-(4-nitrophenyl)but-2-yn-1-one

3,3-Diethoxyprop-1-yne (8.5 ml, 59 mmol) was dissolved in THF (100 ml).The solution was cooled to −70° C., and nBuLi (19 ml of 2.5 M soln inhexanes, 47.5 mmol) was added over 5 min. The solution was warmed to 0°C. for 15 min, then cooled to −70 ° C. again. A solution ofN-methoxy-N-methyl-4-nitrobenzamide (Intermediate 8, 8.04 g, 38.1 mmol)in THF (50 ml) was added dropwise over 15 min. The solution was warmedto 0° C. after 15 min, and held there for 45 min. The reaction mixturewas poured into 1M HCl, extracted with ethyl acetate and dried oversodium sulfate. Purification by chromatography on silica gel elutingwith 30 to 50% dichloromethane: hexane, gave the title compound as alight orange oil which solidified on standing (7.14 g).¹H-NMR 500 MHz (DMSO-d₆) δ: 1.23 (m, 6H); 3.64-3.76 (m, 4H); 5.77 (s,1H); 8.28 (d, 2H); 8.45 (d, 2H).Intermediate 10: 4-r5-(Diethoxymethyl)-1-methyl-1H-pyrazol-3-vllaniline

4,4-Diethoxy-1-(4-nitrophenyl)but-2-yn-1-one (Intermediate 9, 5.77 g,22.4 mmol), methylhydrazine (1.2 ml, 22.4 mmol), and ethanol (100 ml)were combined and warmed at 70° C. for 45 min. THF (50 ml) and palladiumon carbon (10%, 100 mg) were added. The suspension was stirred under 1atmosphere of hydrogen gas for 16 hrs. The mixture was filtered andevaporated to give the title compound as a light yellow solid (5.54 g).¹H-NMR 500 MHz (DMSO-d₆) δ: 1.18 (t, 6H); 3.57 (m, 4H); 3.79 (s, 3H);5.15 (s, 2H); 5.69 (s, 1H); 6.46 (s, 1H); 6.57 (d, 2H); 7.44 (d, 2H).Intermediate 11: Benzyl4-[5-(diethoxymethyl)-1-methyl-1H-pyrazol-3-yl]phenylcarbamate

4-[5-(Diethoxymethyl)-1-methyl-1H-pyrazol-3-yl]aniline (Intermediate 10,5.9 g, 21.5 mmol), and pyridine (4 ml, 50 mmol) were dissolved indichloromethane (25 ml) at 0° C. Benzyl chloroformate (3.8 ml, 26.7mmol) was added slowly over 5 minutes and the resulting mixture wasstirred at 0° C. for 30 min. The mixture was diluted withdichloromethane and washed with 1M HCl, saturated NaCl, then dried oversodium sulfate and evaporated give the title compound as a thick lightorange oil (9.6 g).¹H-NMR 500 MHz (DMSO-d₆) δ: 1.17 (t, 6H); 3.59 (m, 4H); 3.83 (s, 3H);5.18 (s, 2H); 5.72 (s, 1H); 6.63 (s, 1H); 7.35-7.50 (m, 7H); 7.70 (d,2H); 9.84 (s, 1H).Intermediate 12:(5R)-3-{4-[5-(Dimethoxymethyl)-1-methyl-1H-pyrazol-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

Benzyl 4-[5-(diethoxymethyl)-1-methyl-1H-pyrazol-3-yl]phenylcarbamate(Intermediate 11, 8.29 g, 20.2 mmol), was dissolved in TBF (150 ml) andcooled to −70° C. nBuLi (15 ml of a 1.6 M solution in hexanes, 24 mmol)was added dropwise over 10 min. After 25 min at −70° C.,(2R)-oxiran-2-ylmethyl butyrate (3.7 ml, 26.2 mmol) was added and thesolution was allowed to warm slowly to room temperature over 16 hours.The mixture was poured into 0.25M HCl and extracted with ethyl acetate,the organic layer was washed with saturated NaCl, dried over sodiumsulfate and evaporated to give the crude product which was partiallyhydrolysed to the aldehyde. The crude product was dissolved in 1:1 THF:methanol (12 ml), trimethyl orthoformate (2.6 ml, 24 mmol) andcamphorsulfonic acid (100 mg, 0.4 mmol) were added and the solution waswarmed at 50° C. for 1 hour. Triethylamine (0.5 ml) was added and thesolution was evaporated and purified by chromatography on silica gel,eluting with 60-100% ethyl acetate/hexane, to give the title compound asa white solid (3.47 g).¹H-NMR 500 MHz (DMSO-d₆) δ: 3.32 (s, 3H); 3.34 (s, 3H); 3.60 (m, 1H);3.69 (m, 1H); 3.84 (s, 3H); 3.86 (dd, 1H); 4.13 (t, 1H); 4.71 (m, 1H);5.23 (t, 1H); 5.65 (s, 1H); 6.73 (s, 1H); 7.61 (d, 2H); 7.81 (d, 2H).Intermediate 13:3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5-carbaldehyde

(5R)-3-{4-[5-(Dimethoxymethyl)-1-methyl-1H-pyrazol-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one(Intermediate 12, 2 g, 5.76 mmol) was dissolved in dichloromethane (30ml) and THF (10 ml) at 0° C. Triethylamine (1.2 ml, 8.7 mmol) andmethanesulfonyl chloride (0.55 ml, 7.08 mmol) were added and the mixturewas stirred at 0° C. for 1 hour. The mixture was poured into water,washed with saturated NaCl, 1M HCl, dried over sodium sulfate andevaporated to give the crude mesylate. The mesylate was taken up intoDMF (20 ml), then sodium azide (0.54 g, 8.3 mmol), 18-crown-6 (80 mg,0.3 mmol) and tetra(nbutyl)ammonium iodide (100 mg, 0.27 mmol) wereadded. The solution was heated at 90° C. for 16 hours, diluted withethyl acetate, washed with water, saturated NaCl and dried over sodiumsulfate. Evaporation gave the crude azide. The azide was dissolved inmethylene chloride (20 ml), trifluoroacetic acid (20 ml) and water (0.2ml) were added and the mixture was stirred for 30 minutes at roomtemperature. Evaporation followed by chromatography on silica gel,eluting with 50 to 100% ethyl acetate: hexane gave the title compound asa yellow solid (1.02 g).¹H-NMR 500 MHz (DMSO-d₆) δ: 3.72-3.86 (m, 3H); 4.18 (s, 1H); 4.20 (m,1H); 4.93 (m, 1H); 7.51 (s, 1H); 7.66 (d, 2H); 7.90 (d, 2H); 9.96 (s,1H).Intermediate 14:3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5-carbonitrile

3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5carbaldehyde (Intermediate 13, 500 mg, 1.53 mmol) was dissolved indioxane (8 ml), ethanol (4 ml), hydroxylamine hydrochloride (130 mg,1.87 mmol) and a solution of sodium carbonate (100 mg, 0.94 mmol) inwater (3 ml) were added and the resulting suspension was warmed toapproximately 50° C. for 1-2 minutes to give a clear solution. Thesolution was stirred at room temperature for 15 minutes, poured intowater, extracted with ethyl acetate, dried over sodium sulfate andevaporated to give the crude oxime as an off white solid (515 mg). Theoxime was dissolved in THF (20 ml) and cooled to 0° C. Thionyl chloride(0.55 ml, 7.53 mmol) was added and the resulting mixture was stirred at0° C. for 2 hours. The reaction mixture was evaporated and purified bychromatography on silica gel, eluting with 30 to 50% ethyl acetate:hexane, to give the title compound as a white solid (470 mg).¹H-NMR 500 MHz (DMSO-d₆) δ: 3.70-3.86 (m, 3H); 4.08 (s, 3H); 4.21 (t,1H); 4.93 (m, 1H); 7.63 (s, 1H); 7.67 (d, 2H); 7.87 (d, 2H).

EXAMPLE 6

1-Methyl-3-{4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-1H-pyrazole-5-carbaldehyde

3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5carbaldehyde (Intermediate 13, 50 mg, 0.15 mmol),bicyclo[2.2.1]hepta-2,5-diene (0.17 ml, 1.58 mmol) and dioxane (1 ml)were combined and warmed to 90° C. for 4.5 hours. The mixture wasevaporated and purified by chromatography on silica gel, eluting withethyl acetate to give the title compound as a white solid (25 mg).MS (ESP): 353 (M+1) for C₁₇H₁₆N₆O₃¹H-NMR 500 MHz (DMSO-d₆) δ: 3.96 (dd, 1H); 4.17 (s, 3H); 4.29 (t, 1H);4.87 (d, 2H); 5.17 (m, 1H); 7.51 (s, 1H); 7.58 (d, 2H); 7.79 (s, 1H);7.88 (d, 2H); 8.20 (s, 1H); 9.96 (s, 1H).

EXAMPLE 7

(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

(5R)-3-{3-Fluoro-4-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Intermediate 15, 1.12 g, 2.49 mnol) was dissolved in trifluoroaceticacid (20 ml) and stirred at 65° C. overnight. The solution wasconcentrated then diluted with water until a precipitate formed. Thelight green solid was recrystallized using acetone and methanol to givethe desired product as a beige solid (0.782 g).MS (ESP): 330 (MH⁺) for C₁₄H₁₂FN₇O₂¹H-NMR 500 MHz (DMSO-d₆): 3.96-3.99 (m, 1H); 4.29-4.32 (t, 1H); 4.88 (d,2H); 5.17-5.22 (m, 1H); 7.42 (d, 1H); 7.60 (d, 1H); 7.79 (s, 1H); 7.99(br s, 0.6H); 8.08 (br s,0.6H); 8.11 (br s, 0.4H); 8.20 (s, 1H); 8.34(br s, 0.4H) 15.18 (br s, 0.6H); 15.49 (br s, 0.4H).The intermediates for this compound were prepared as follows:Intermediate 15:(5R)-3-{3-Fluoro-4-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

(5R)-3-(4-Ethynyl-3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Intermediate 16, 1.0 g, 3.5 mmol) was dissolved in 1,4-dioxane (35 ml).1-Azido-4-methoxybenzene(2.9 g, 18 mmol) was added and the reaction was stirred at 100° C.overnight. Additional 1-azido-4-methoxybenzene (2.0 g, 12 mmol) wasadded and the solution was stirred an additional six days. The solutionwas adsorbed onto silica gel and chromatographed eluting with 40% ethylacetate/hexanes, to ethyl acetate, followed by 2-10% methanol/ethylacetate. Relevant fractions were combined and recrystallized frommethanol (300 ml), ethyl acetate (300 ml), acetone (200 ml), and ethanol(100 ml) to give the desired product (408 mg) as a beige solid.MS (ESP): 450 (MH⁺) for C₂₂H₂₀FN₇O₃¹H-NMR 500 MHz (DMSO-d₆) 3.76 (s, 3H); 3.97 (dd, 1H); 4.29 (t, 1H); 4.87(d, 2H); 5.16-5.20 (m, 1H); 5.6 (s, 2H); 6.96 (s, 1H); 6.97 (s, 1H);7.37 (s, 1H); 7.39 (s, 1H); 7.41 (d, 1H); 7.59 (d, 1H); 7.79 (s, 1H);8.11 (t, 1H); 8.20 (s, 1H); 8.46 (s, 1H).Intermediate 16:(5R)-3-(4-Ethynyl-3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

(5R)-3-{3-Fluoro-4-[(trimethylsilyl)ethynyl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Intermediate 17, 6.1 g, 17 mmol) was stirred in methanol (155 ml). 1 NPotassium hydroxide (30 ml) was added and the reaction was stirred for20 minutes. The solution was diluted with methylene chloride (200 ml)then acidified to pH 1.5 using 1 N hydrochloric acid. The solution wasdiluted with water and the compound was extracted using methylenechloride. The organic layer was washed with water, dried (magnesiumsulfate), filtered, and concentrated. The orange solid was adsorbed ontosilica gel and chromatographed using ethyl acetate to give the titlecompound as a yellow solid (2.3 g).MS (ESP): 287 (MH⁺) for C₁₄H₁₁FN₄O₂¹H-NMR 300 MHz (DMSO-d₆): 3.94 (dd, 1H); 4.27 (t, 1H); 4.46 (s, 1H);4.86 (d, 2H); 5.17-5.19 (m, 1H); 7.33 (dd, 1H); 7.53 (dd, 1H); 7.58 (s,1H); 7.78 (s, 1H); 8.19 (s, 1H).Intermediate 17:(5R)-3-{3-Fluoro-4-[(trimethylsilyl)ethynyl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Intermediate 6, 0.50 g, 1.3 mmol),tris(dibenzylideneacetone)dipalladium (0) (24 mg, 0.026 mmol),tri-2-furylphosphine (12 mg, 0.05 mmol), and copper iodide (5.0 mg,0.013 mmol) were combined in a flask and degassed. Tetrahydrofuran (7.5ml), triethylamine (0.54 g, 5.4 mmol) and a minimal amount of1-methyl-2-pyrrolidinone (1.5 ml) were added to obtain a brown solution.(Trimethylsilyl)acetylene (0.18 g, 1.8 mmol) was added and the reactionwas stirred at room temperature overnight. The solution was adsorbedonto silica gel and chromatographed eluting with ethyl acetate to givethe title compound as a brown oil (1.2 g) (contains1-methyl-2-pyrrolidinone).MS (ESP): 359 (MF⁺) for C₁₇H₁₉FN₄O₂Si¹H-NMR 500 MHz (DMSO-d₆): 0.25 (s, 9H); 3.94 (dd, 1H); 4.25-4.29 (m,1H); 4.86 (d, 2H); 5.17-5.19 (m, 1H); 7.32 (dd, 1H); 7.53 (dd, 1H); 7.56(t, 1H); 7.78 (s, 1H); 8.19 (s, 1H).

EXAMPLE 8

(5R)-3-[3-Fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Example 7, 1.7 g, 5.2 mmol) was stirred in N,N-dimethylformamide at 0°C. Sodium hydride (0.40 g, 10 mol) was added and the mixture was stirredfor 30 minutes. Iodomethane (0.88 g, 6.2 mmol) was added and thereaction was stirred for three days, slowly warming to room temperature.The mixture was diluted with water and extracted using ethyl acetate.The organic layer was washed with water, dried (magnesium sulfate) andconcentrated under vacuum. The residue was recrystallized using ethylacetate to give a mixture of products (0.42 g) as beige solid. The solidwas dissolved in dimethylsulfoxide (5 ml), acetonitrile (12 ml) andwater (1 ml) and the isomers were separated using Gilson HPLC.Peaks 1 and 2 were collected, concentrated and lyophilized to give alight yellow solid (Example 8, peak 1, 213 mg; Example 9, peak 2, 207mg). NOE experiments were used to distinguish the two isomers with themethyl groups of peak 1 and 2 corresponding to the 1 and 2 positions ofthe nitrogen, respectively.MS (ESP): 344 (MH⁺) for C₁₅H₁₄FN₇O₂¹H-NMR 500 MHz (DMSO-d₆): 3.95-3.98 (m, 1H); 4.13 (s, 3H); 4.30 (t, 1H);4.88 (s, 2H); 5.17-5.21 (m, 1H); 7.41 (d, 1H); 7.60 (d, 1H); 7.79 (s,1H); 8.12 (t, 1H); 8.20 (s, 1H); 8.39 (s, 1H).

EXAMPLE 9

(5R)-3-[3-Fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)phenyI]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

MS (ESP): 344 (MH⁺) for C₁₅H₁₄FN₇O₂¹H-NMR 500 MHz (DMSO-d₆): 3.96-3.99 (m, 1H); 4.24 (s, 3H); 4.30 (t, 1H);4.88 (s, 2H); 5.18-5.21 (m, 1H); 7.42 (d, 1H); 7.59 (d, 1H); 7.79 (s,1H); 7.94 (t, 1H); 8.04 (d, 1H); 8.20 (s, 1H).

EXAMPLE 10

(4-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-1H-1,2,3-triazol-1-yl)acetonitrile

(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(Example 7, 1.5 g, 4.6 mmol) was stirred in N,N-dimethylformamide at 0°C. Sodium hydride (0.35 g, 9.2 mmol) was added and the mixture wasstirred 30 minutes. Bromoacetonitrile (0.66 g, 5.5 mmol) was added andthe reaction was stirred overnight, slowly warming to room temperature.Starting material was present so additional bromoacetonitrile (0.33 g,2.8 mmol) was added and the reaction was stirred for two additionaldays. The mixture was diluted with water and extracted using ethylacetate. The organic layer was washed with water, dried (magnesiumsulfate) and concentrated under vacuum to give a yellow solid (1.84 g).The solid was dissolved in dimethylsulfoxide (18 ml) and water (5 ml)and the isomers were separated using Gilson HPLC. Peaks 1 and 2 werecollected, concentrated and lyophilized to give a light yellow solid(Example 10, peak 1, 36 mg; Example 11, peak 2, 182 mg). NOE experimentswere used to distinguish the two isomers with the cyano group of peaks 1and 2 corresponding to the 1 and 2 positions of the nitrogen,respectively.MS (ESP): 369 (MH⁺) for C₁₆H₁₃FN₈O₂¹H-NMR 500 MHz (DMSO-d): 3.98 (dd, 1H); 4.31 (t, 1H); 4.88 (d, 2H);5.17-5.22 (m, 1H); 5.88 (s, 2H); 7.44 (d, 1H); 7.63 (d, 1H); 7.79 (s,1H); 8.15 (t, 1H); 8.21 (s, 1H); 8.59 (d, 1H).

EXAMPLE 11

(4-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-2H-1,2,3-triazol-2-yl)acetonitrile

MS (ESP): 369 (MH⁺) for C₁₆H₁₃FN₈O₂¹H-NMR 500 MHz (DMSO-d₆) 3.98 (dd, 1H); 4.31 (t, 1H); 4.89 (d, 2H);5.18-5.23 (m, 1H); 6.01 (s, 2H); 7.46 (d, 1H); 7.62 (d, 1H); 7.79 (s,1H); 7.96 (t, 1H); 8.21 (s, 1H); 8.26 (d, 1H).

1. A compound of the formula (I), or a pharmaceutically-acceptable salt,or an in-vivo-hydrolysable ester thereof,

wherein —N-HET is selected from the structures (Ia) to (If) below:—

Q is selected from Q1 to Q6:—

R₂ and R₃ are independently selected from H, F, Cl, CF₃, OMe, SMe, Meand Et; B₁ is O or S; T is selected from the groups in (TAa1) to(TAa12):

wherein: R^(6h) is selected from hydrogen, (1-4C)alkyl,(1-4C)alkoxycarbonyl, (1-4C)alkanoyl, carbamoyl and cyano; R^(4h) andR^(5h) are independently selected from hydrogen, halo, trifluoromethyl,cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)_(q)-(q is 0, 1 or 2),(1-4C)alkanoyl, (1-4C)alkoxycarbonyl, benzyloxy-(1-4C)alkyl,(2-4C)alkanoylamino, —CONRcRv and —NRcRv wherein any (1-4C)alkyl groupcontained in the preceding values for R^(4h) and R^(5h) is optionallysubstituted by up to three substituents independently selected fromhydroxy (not on C1 of an alkoxy group, and excluding geminaldisubstitution), oxo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy,(2-4C)alkanoyloxy, hydroxyimino, (1-4C)alkoxyimino,(1-4C)alkylS(O)_(q)-(q is 0, 1 or 2), (1-4C)alkylSO₂-NRv—,(1-4C)alkoxycarbonyl, —CONRcRv, and —NRcRv (not on C1 of an alkoxygroup, and excluding geminal disubstitution); wherein Rv is hydrogen or(1-4C)alkyl and Rc is as hereinafter defined; R^(4h) and R^(5h) mayfurther be independently selected from (1-4C)alkyl {optionallysubstituted by one, two or three substituents independently selectedfrom hydroxy (excluding geminal disubstitution), oxo, trifluoromethyl,cyano, nitro, (1-4C)alkoxy, (2-4C)alkanoyloxy, phosphoryl [—O-P(O)(OH)₂,and mono- and di-(1-4C)alkoxy derivatives thereof], phosphiryl[—O-P(OH)₂ and mono- and di-(1-4C)alkoxy derivatives thereof],hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)-(q is 0, 1 or 2),(1-4C)alkylSO₂-NRv—, (1-4C)alkoxycarbonyl, —CONRcRv, —NRcRv (excludinggeminal disubstitution), ORc, and phenyl (optionally substituted by one,two or three substituents independently selected from (1-4C)alkyl,(1-4C)alkoxy and halo)}; wherein Rv is hydrogen or (1-4C)alkyl and Rc isas hereinafter defined; and wherein any (1-4C)alkyl group contained inthe immediately preceding optional substituents (when R^(4h) and R^(5h)are independently (1-4C)alkyl) is itself optionally substituted by up tothree substituents independently selected from hydroxy (not on C1 of analkoxy group, and excluding geminal disubstitution), oxo,trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (2-4C)alkanoyloxy,hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)-(q is 0, 1 or 2),(1-4C)alkylSO₂-NRv—, (1-4C)alkoxycarbonyl, —CONRcRv, and —NRcRv (not onC1 of an alkoxy group, and excluding geminal disubstitution); wherein Rvis hydrogen or (1-4C)alkyl and Rc is as hereinafter defined; or R^(4h)is selected from one of the groups in (TAaa) to (TAab) below, or (whereappropriate) one of R^(4h) and R^(5h) is selected from the above list.ofR^(4h) and R^(5h) values, and the other is selected from one of thegroups in (TAaa) to (TAab) below:— (TAaa) a group of the formula (TAaa1)

wherein Z⁰ is hydrogen or (1-4C)alkyl; X⁰ and Y⁰ are independentlyselected from hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl, halo, cyano,nitro, (1-4C)alkylS(O)_(q)-(q is 0, 1 or 2), RvRwNSO₂—, trifluoromethyl,pentafluoroethyl, (1-4C)alkanoyl and —CONRvRw [wherein Rv is hydrogen or(1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl]; (TAab) an acetylene of theformula —≡—H or —≡—(1-4C)alkyl; wherein Rc is selected from groups (Rc1)to (Rc2) :— (Rc1) (1-6C)alkyl {optionally substituted by one or more(1-4C)alkanoyl groups (including geminal disubstitution) and/oroptionally monosubstituted by cyano, (1-4C)alkoxy, trifluoromethyl,(1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR1 definedhereinafter), (1-4C)alkylS(O)_(q)-(q is 0, 1 or 2); or, on any but thefirst carbon atom of the (1-6C)alkyl chain, optionally substituted byone or more groups (including geminal disubstitution) each independentlyselected from hydroxy and fluoro, and/or optionally monosubstituted byoxo, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O)_(p)NH— or(1-4C)alkylS(O)_(p)-((1-4c)alkyl)N— (p is 1 or 2)}; (Rc2) R¹³CO—,R¹³SO₂— or R¹³CS— wherein R¹³ is selected from (Rc2a) to (Rc2d):— (Rc2a)hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl and —NRvRw [wherein Rvis hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl]; (Rc2b)(1-10C)alkyl {optionally substituted by one or more groups (includinggeminal disubstitution) each independently selected from hydroxy,(1-10C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, carboxy,phosphoryl [—O-P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivativesthereof], phosphiryl [—O-P(OH)₂ and mono- and di-(1-4C)alkoxyderivatives thereof], and amino; and/or optionally substituted by onegroup selected from phosphonate [phosphono, —P(O)(OH)₂, and mono- anddi-(1-4C)alkoxy derivatives thereof], phosphinate [—P(OH)₂ and mono- anddi-(1-4C)alkoxy derivatives thereof], cyano, halo, trifluoromethyl,(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino,di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylaminocarbonyl,di((1-4C)alkyl)aminocarbonyl, (1-4C)alkylS(O)_(p)NH—,(1-4C)alkylS(O)_(p)-((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O)pNH—,fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, (1-4C)alkylS(O)_(q)— [the(1-4C)alkyl group of (1-4C)alkylS(O)_(q)— being optionally substitutedby one substituent selected from hydroxy, (1-4C)alkoxy, (1-4C)alkanoyl,phosphoryl [—O-P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivativesthereof], phosphiryl [—O-P(OH)₂ and mono- and di-(1-4C)alkoxyderivatives thereof], amino, cyano, halo, trifluoromethyl,(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, carboxy,(1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino,(1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino,(1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl,(1-4C)alkylS(O)_(p)NH—, (1-4C)alkylS(O)p-((1-4C)alkyl)N—, and(1-4C)alkylS(O)q-; (Rc2c) R¹⁴C(O)O(1-6C)alkyl wherein R¹⁴ is AR1, AR2,(1-4C)alkylamino (the (1-4C)alkyl group being optionally substituted by(1-4C)alkoxycarbonyl or by carboxy), benzyloxy-(1-4C)alkyl or(1-10C)alkyl {optionally substituted as defined for (Rc2b)}; (Rc2d)R¹⁵O— wherein R¹⁵ is benzyl, (1-6C)alkyl {optionally substituted asdefined for (Rc2c)} or AR2b; wherein AR1 is an optionally substitutedphenyl or optionally substituted naphthyl; AR2 is an optionallysubstituted 5- or 6-membered, fully unsaturated monocyclic heteroarylring containing up to four heteroatoms independently selected from O, Nand S (but not containing any O13 O, O—S or S—S bonds), and linked via aring carbon atom, or a ring nitrogen atom if the ring is not therebyquaternised; AR2a is a partially hydrogenated version of AR2, linked viaa ring carbon atom or linked via a ring nitrogen atom if the ring is notthereby quaternised; AR2b is a fully hydrogenated version of AR2, linkedvia a ring carbon atom or linked via a ring nitrogen atom.
 2. Thecompound of claim 1, wherein Q is Q1.
 3. The compound of claim 1,wherein —N-HET is 1,2,3-triazol-1-yl or tetrazol-2-yl.
 4. The compoundof claim 1, wherein R² and R³ are independently hydrogen or fluoro. 5.The compound of claim 1, wherein T is selected from TAa1 to TAa4, TAa5,TAa7 and TAa8.
 6. The compound of claim 1, which is a compound offormula (IB

wherein —N-HET is 1,2,3-triazol-1-yl or tetrazol-2-yl; R² and R³ areindependently hydrogen or fluoro; T is selected from TAa1, TAa5, TAa7and TAa8; R^(6h) is hydrogen or (1-4C)alkyl; R^(4h) and R^(5h) areindependently selected from hydrogen, cyano, hydroxy(1-4C)alkyl,cyano(1-4C)alkyl, phosphoryl(1-4C)alkyl, benzyl (optionally substitutedon the phenyl ring by one substituent selected from halo, methyl andmethoxy), (1-4C)alkyl, (1-4C)alkyl substituted with ORc (wherein Rc isR¹³CO and R¹³ is selected from Rc2b), (1-4C)alkanoyl and(1-4C)alkoxycarbonyl.
 7. (canceled)
 8. A method for producing anantibacterial effect in a warm blooded animal which comprisesadministering to said animal an effective amount of a compound ofclaim
 1. 9. (canceled)
 10. (canceled)
 11. A pharmaceutical compositionwhich comprises a compound of claim 1, and a pharmaceutically-acceptablediluent or carrier.
 12. A process for the preparation of a compound offormula (I) as claimed in claim 1 or pharmaceutically acceptable saltsor in-vivo hydrolysable esters or pro-drugs thereof, which processcomprises one of processes (a) to (g): (a) by modifying a substituentin, or introducing a new substituent into, the substituent group Q ofanother compound of formula (I); or (b) by reaction of a compound offormula (II):

wherein Y is a displaceable group with a compound of the formula (III):—N-HET  (III) wherein —N-HET (of formula (Ia) to (If) optionallyprotected) is HN-HET (free-base form) or ^(—)N-HET anion formed from thefree base form; or (c) by reaction of a compound of the formula (IV)Q-Z  (IV) wherein Z is an isocyanate, amine or urethane group with anepoxide of the formula (V) wherein the epoxide group serves as a leavinggroup at the terminal C-atom and as a protected hydroxy group at theinternal C-atom; or with a related compound of formula (VI) where thehydroxy group at the internal C-atom is protected and where the leavinggroup Y at the terminal C-atom is a leaving group;

or (d) (i) by coupling, using catalysis by transition metals, of acompound of formula (VII):

wherein Y′ is a group —N-HET as hereinbefore defined, X is a replaceablesubstituent; with a compound of the formula (VIII), or an analoguethereof, which is suitable to give a T substituent as defined by(TAa1-TAa12) in which the link is via an sp² carbon atom (D═CH═C-Lgwhere Lg is a leaving group; or as in the case of reactions carried outunder Heck reaction conditions Lg may also be hydrogen)

where T₁ and T₂ may be the same or different and comprise a precursor toa ring of type T as hereinbefore defined, or T₁ and T₂ may together withD form a ring of type T as hereinbefore defined; (d) (ii) by coupling,using catalysis by transition metals, of a compound of formula (VIIA):

wherein Y′ is a group HET as hereinbefore defined, with a compound[Aryl]-X where X is a replaceable substituent; (e) Where N-HET is1,2,3-triazole by cycloaddition via the azide (wherein Y in (II) isazide), with acetylene or masked acetylene; (f) Where N-HET is1,2,3-triazole by synthesis with a compound of formula (IX), namely thearenesulfonylhydrazone of acetaldehyde, by reaction of a compound offormula (II) where Y=NH₂ (primary amine);

(g) Where N-HET is 1,2,3-triazole by cycloaddition via the azide(wherein Y in (II) is azide) with acetylene using Cu(I) catalysis in togive the N-1,2,3-triazole;

and thereafter if necessary: i) removing any protecting groups; ii)forming a pro-drug (for example an in-vivo hydrolysable ester); and/oriii) forming a pharmaceutically-acceptable salt.
 13. A compound which is(5R)-3-[3-Fluoro-4-(3-methylisoxazol-5-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;Ethyl5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazole-3-carboxylate;(5R)-3-{3-Fluoro-4-[3-(hydroxymethyl)isoxazol-5-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazol-3-yl)methyldihydrogen phosphate;1-Methyl-3-{4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-1H-pyrazole-5-carbonitrile;1-Methyl-3-{4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-1H-pyrazole-5-carbaldehyde;(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5R)-3-[3-Fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5R)-3-[3-Fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(4-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-1H-1,2,3-triazol-1-yl)acetonitrile;or(4-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}-2H-1,2,3-triazol-2-yl)acetonitrile.